Kinase inhibitors

ABSTRACT

Compounds of formula (I) described herein are p38 MAPK inhibitors and are useful as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.13170937.0 filed on Jun. 6, 2013, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds and compositions that are p38MAPK inhibitors and which are useful as anti-inflammatory agents in thetreatment of, inter alia, diseases of the respiratory tract.

2. Discussion of the Background

Mitogen activated protein kinases (MAPK) constitute a family ofproline-directed serine/threonine kinases that activate their substratesby dual phosphorylation. There are four known human isoforms of p38 MAPkinase, p38α, p38β, p38γ, and p38δ. The p38 kinases, which are alsoknown as cytokine suppressive anti-inflammatory drug binding proteins(CSBP), stress activated protein kinases (SAPK) and RK, are responsiblefor phosphorylating (Stein et al., Ann. Rep. Med Chem., 1996, 31,289-298, which is incorporated herein by reference in its entirety) andactivating transcription factors (such as ATF-2, MAX, CHOP and C/ERPb)as well as other kinases (such as MAPKAP-K2/3 or MK2/3), and arethemselves activated by physical and chemical stress (e.g. UV, osmoticstress), pro-inflammatory cytokines and bacterial lipopolysaccharide(LPS) (Herlaar E. & Brown Z., Molecular Medicine Today, 1999, 5,439-447, which is incorporated herein by reference in its entirety). Theproducts of p38 phosphorylation have been shown to mediate theproduction of inflammatory cytokines, including tumor necrosis factoralpha (TNF α) and interleukin-(IL-)-1, and cyclooxygenase-2 (COX-2).IL-1 and TNFα are also known to stimulate the production of otherproinflammatory cytokines such as IL-6 and IL-8.

IL-1 and TNFα are biological substances produced by a variety of cells,such as monocytes or macrophages. IL-1 has been demonstrated to mediatea variety of biological activities thought to be important inimmunoregulation and other physiological conditions such as inflammation(e.g. Dinarello et al., Rev. Infect. Disease, 1984, 6, 51, which isincorporated herein by reference in its entirety). Excessive orunregulated TNF production (particularly TNFα) has been implicated inmediating or exacerbating a number of diseases, and it is believed thatTNF can cause or contribute to the effects of inflammation in general.IL-8 is a chemotactic factor produced by several cell types includingmononuclear cells, fibroblasts, endothelial cells, and keratinocytes.Its production from endothelial cells is induced by IL-1, TNF, orlipopolysaccharide (LPS). IL-8 stimulates a number of functions invitro. It has been shown to have chemoattractant properties forneutrophils, T-lymphocytes and basophils. Increase in IL-8 production isalso responsible for chemotaxis of neutrophils into the inflammatorysite in vivo.

Inhibition of signal transduction via p38, which in addition to IL-1,TNF α nd IL-8 described above is also required for the synthesis and/oraction of several additional pro-inflammatory proteins (e.g., IL-6,GM-CSF, COX-2, collagenase and stromelysin), is expected to be a highlyeffective mechanism for regulating the excessive and destructiveactivation of the immune system. This expectation is supported by thepotent and diverse anti-inflammatory activities described for p38 kinaseinhibitors (Badger et al., J. Pharm. Exp. Thera., 1996, 279, 1453-1461;Griswold et al, Pharmacol. Comm., 1996, 7, 323-229, which areincorporated herein by reference in their entireties). In particular,p38 kinase inhibitors have been described as potential agents fortreating rheumatoid arthritis. In addition to the links between p38activation and chronic inflammation and arthritis, there is also dataimplicating a role for p38 in the pathogenesis of airway diseases inparticular COPD and asthma. Stress stimuli (including tobacco smoke,infections or oxidative products) can cause inflammation within the lungenvironment. Inhibitors of p38 have been shown to inhibit LPS andovalbumin induced airway TNF-α IL-1β, IL-6, IL-4, IL-5 and IL-13 (Haddadet al, Br. J. Pharmacol., 2001, 132 (8), 1715-1724; Underwood et al, Am.J. Physiol. Lung Cell. Mol. 2000, 279, 895-902; Duan et al., 2005 Am. J.Respir. Crit. Care Med., 171, 571-578; Escott et al Br. J. Pharmacol.,2000, 131, 173-176; Underwood et al., J. Pharmacol. Exp. Ther. 2000,293, 281-288, which are incorporated herein by reference in theirentireties). Furthermore, they significantly inhibit neutrophilia andthe release of MMP-9 in LPS, ozone or cigarette smoke animal models.There is also a significant body of preclinical data highlighting thepotential benefits of inhibition of the p38 kinase that could berelevant in the lung (Lee et al., Immunopharmacology, 2000, 47, 185-200,which is incorporated herein by reference in its entirety). Thus,therapeutic inhibition of p38 activation may be important in theregulation of airway inflammation.

The implication of the p38MAPK pathway in various diseases has beenreviewed by P. Chopra et al. (Expert Opinion on Investigational Drugs,2008, 17(10), 1411-1425, which is incorporated herein by reference inits entirety). It is believed that the compounds of the presentinvention can be used to treat p38 mediated diseases such as: chronicobstructive pulmonary disease (COPD), asthma, chronic or acutebronchoconstriction, bronchitis, acute lung injury and bronchiectasis,pulmonary artery hypertension, tuberculosis, lung cancer, inflammationgenerally (e.g. inflammatory bowel disease), arthritis,neuroinflammation, pain, fever, fibrotic diseases, pulmonary disordersand diseases (e.g., hyperoxic alveolar injury), cardiovascular diseases,post-ischemic reperfusion injury and congestive heart failure,cardiomyopathy, stroke, ischemia, reperfusion injury, renal reperfusioninjury, brain edema, neurotrauma and brain trauma, neurodegenerativedisorders, central nervous system disorders, liver disease andnephritis, gastrointestinal conditions, ulcerative diseases, Crohn'sdisease, ophthalmic diseases, ophthalmological conditions, glaucoma,acute injury to the eye tissue and ocular traumas, diabetes, diabeticnephropathy, skin-related conditions, myalgias due to infection,influenza, endotoxic shock, toxic shock syndrome, autoimmune disease,graft rejection, bone resorption diseases, multiple sclerosis,psoriasis, eczema, disorders of the female reproductive system,pathological (but non-malignant) conditions, such as hemangiomas,angiofibroma of the nasopharynx, and avascular necrosis of bone, benignand malignant tumors/neoplasia including cancer, leukaemia, lymphoma,systemic lupus erythematosus (SLE), angiogenesis including neoplasia,haemorrhage, coagulation, radiation damage, and/or metastasis. Chronicrelease of active TNF can cause cachexia and anorexia, and TNF can belethal. TNF has also been implicated in infectious diseases. Theseinclude, for example, malaria, mycobacterial infection and meningitis.These also include viral infections, such as HIV, influenza virus, andherpes virus, including herpes simplex virus type-1 (HSV-1), herpessimplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zostervirus (VZV), Epstein-Barr virus, human herpes virus-6 (HHV-6), humanherpesvirus-7 (HHV7), human herpesvirus-8 (HHV-8), pseudorabies andrhinotracheitis, among others.

Known P38 kinase inhibitors have been reviewed by G. J. Hanson (ExpertOpinions on Therapeutic Patents, 1997, 7, 729-733) J Hynes et al.(Current Topics in Medicinal Chemistry, 2005, 5, 967-985), C. Dominguezet al (Expert Opinions on Therapeutics Patents, 2005, 15, 801-816) andL. H. Pettus & R. P. Wurtz (Current Topics in Medicinal Chemistry, 2008,8, 1452-1467), which are incorporated herein by reference in theirentireties. P38 kinase inhibitors containing a triazolopyridine motifare known in the art, for example WO 07/091152, WO 04/072072, and WO06/018727, which are incorporated herein by reference in theirentireties.

WO 2010/094956, which is incorporated herein by reference in itsentirety, discloses triazolopyridine derivatives of formula (I) as beingp38 MAP Kinase inhibitors:

In such compounds, A represents an optionally substituted divalentarylene radical, an heteroarylene radical, a (C₅-C₆) divalentcycloalkylene radical having 5 or 6 ring atoms or a pyperidinyleneradical.

Other p38 MAP Kinase inhibitors are described in the co-pendingapplications PCT/EP2011/072375, PCT/EP2012/074446 and PCT/EP2012/074450,which are incorporated herein by reference in their entireties.

The compounds are said to be useful in as anti-inflammatory agents inthe treatment of diseases of the respiratory tract.

However, there remains a need for improved p38 mitogen activated proteinkinase inhibitors.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelp38 mitogen activated protein kinase inhibitors which are useful in thetreatment of inflammatory and obstructive diseases of the respiratorytract.

It is another object of the present invention, to provide novel p38mitogen activated protein kinase inhibitors which show an appropriatedevelopability profile on inhalatory administration to effectively treatrespiratory obstructive or inflammatory diseases. It is to be understoodthat such profile may be achieved in a number of different ways bymodulation of specific properties; by way of example, it could beachieved by administration of a low effective dose of the drug thuslimiting side effects or via a long duration of action in the lungswhich may reduce the frequency of administration.

It is another object of the present invention to provide novel methodsof treating certain diseases and/or conditions by administering such ap38 mitogen activated protein kinase inhibitor.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discovery ofthe compounds of formula (I) described below.

The compounds of the present invention are inhibitors of p38 mitogenactivated protein kinase (“p38 MAPK”, “p38 kinase” or “p38”), includingp38a kinase, and are inhibitors of cytokine and chemokine productionincluding TNFα and IL-8 production. They have a number of therapeuticapplications, in the treatment of inflammatory diseases, particularlyallergic and non-allergic airways diseases, more particularlyobstructive or inflammatory airways diseases such as chronic obstructivepulmonary disease (“COPD”) and asthma. They are therefore particularlysuited for pulmonary delivery, by inhalation by nose or mouth.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the invention there is provided a compound of formula (I),or a pharmaceutically acceptable salt thereof:

wherein:

W is a heteroatom selected from N or O, wherein N is substituted with—H, C₁-C₆ alkyl or C₃-C₅ cycloalkyl;

Y is selected in the group consisting of: a group —S(O)_(p)— wherein pis 0, 1 or 2; a group —O(CR³R⁴)_(n)—; a group —(CR⁵R⁶)_(n)—; a group—NR⁷—; a group —OC(O)—; a group —OC(O)NH—; and a group —OC(O)O—;

R³, R⁴, R⁵ and R⁶ are each independently —H, —F or C₁-C₆ alkyl, or,respectively, R³ and R⁴, or R⁵ and R⁶ may form together with the carbonatom to which they are attached a saturated 3-6 membered carbocyclicmonocyclic ring optionally substituted by a group C₁-C₆ alkyl, hydroxylor halo;

n is 0, 1, 2 or 3;

R⁷ is —H, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl wherein such C₁-C₆ alkyl orC₃-C₇ cycloalkyl are optionally substituted by a group C₁-C₃ alkyl,C₃-C₆ cycloalkyl, hydroxyl, —CN or halo;

R¹ is a group selected from (IIa)-(IIc):

R⁸ and R⁹ are each independently —H or C₁-C₆ alkyl, or R⁸ and R⁹ mayform together with the nitrogen atom to which they are attached a4-11-membered saturated monocyclic or a fused or spiro bicyclic ringsystem optionally containing a further heteroatom which is oxygen ornitrogen, said nitrogen atom being optionally substituted by C₁-C₆alkyl; wherein such C₁-C₆ alkyl groups may be optionally substituted bya group C₁-C₆ alkyl, C₃-C₆ cycloalkyl, hydroxyl or halo;

X¹, X², X³, X⁴ and X⁵ are each independently a carbon atom, a nitrogenatom, a group —(CH)— or a group —NH—; such that each combination thereofforms an aromatic ring system;

R¹⁰ is selected from a group consisting of: —H, —CN, —NR^(A)R^(B),—N(R^(C))(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))(C₃-C₇cycloalkylene)-NR^(A)R^(B), —(C₁-C₆alkylene)-NR^(A)R^(B),—(C₃-C₇cycloalkylene)-NR^(A)R^(B), —O—(C₂-C₆alkylene)-NR^(A)R^(B),—O—(C₃-C₇cycloalkylene)-NR^(A)R^(B), —S—(C₂-C₆alkylene)-NR^(A)R^(B),—S—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-OR^(D),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D), —N(R^(C))C(O)NR^(A)R^(B),—C(O)NR^(A)R^(B), —N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—(C₂-C₆alkylene)-OR^(D), —(C₃-C₇cycloalkylene)-OR^(D),—O—(C₂-C₆alkylene)-OR^(D), —O—(C₃-C₇cycloalkylene)-OR^(D),—S—(C₂-C₆alkylene)-OR^(D), —S—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))S(O)₂—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-OR^(D),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))S(O)₂—(C₂-C₆alkylene)-OR^(D),—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-OR^(D), —S(O)₂N(R^(A)R^(B)),—N(R^(C))S(O)₂R^(D), —N(R^(C))C(O)R^(C), —OR^(C), —SR^(C),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl),(C₅-C₇heterocycloalkyl)(C₃-C₆cycloalkyl)-, and C₃-C₇heterocycloalkylcarbonyl; wherein any of such C₁-C₆alkyl,C₃-C₆cycloalkyl, —(C₁-C₆alkylene)- —(C₂-C₆alkylene)-,—(C₃-C₇cycloalkylene)-, —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) and (C₃-C₇heterocycloalkyl)carbonyl portion in the abovelisted groups may be optionally substituted by a group C₁-C₆ alkyl,C₃-C₇ cycloalkyl, hydroxyl or halo;

R¹¹ is linked to X⁴ and is selected from a group consisting of: —H; —CN;C₁-C₆ alkyl which is substituted by a group selected from —CN, —OR^(C),—SR^(C), halo; C₃-C₆cycloalkyl which is substituted by a group selectedfrom C₁-C₄ alkyl, —CN, —OR^(C), —SR^(D), halo; —NR^(A)R^(B),—N(R^(C))(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))(C₃-C₇cycloalkylene)-NR^(A)R^(B), —(C₁-C₆alkylene)-NR^(A)R^(B),—(C₃-C₇cycloalkylene)-NR^(A)R^(B), —O—(C₂-C₆alkylene)-NR^(A)R^(B),—O—(C₃-C₇cycloalkylene)-NR^(A)R^(B), —S—(C₂-C₆alkylene)-NR^(A)R^(B),—S—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-OR^(D),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D), —N(R^(C))C(O)N(R^(A)R^(B)),—C(O)N(R^(A)R^(B)), —N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—O—(C₂-C₆alkylene)-OR^(D), —O—(C₃-C₇cycloalkylene)-OR^(D),—S—(C₂-C₆alkylene)-OR^(D), —S—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))S(O)₂—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-OR^(D),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))S(O)₂—(C₂-C₆alkylene)-OR^(D), —N(R^(C))S(O)₂(C₃-C₇cycloalkylene)-OR^(D), —S(O)₂N(R^(A)R^(B)), —N(R^(C))S(O)₂R^(D),—N(R^(C))C(O)R^(C), OR^(C), SR^(C), —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl),(C₅-C₇heterocycloalkyl)(C₃-C₆cycloalkyl) and (C₃-C₇heterocycloalkyl)carbonyl, wherein any of such C₁-C₆alkyl,C₃-C₆cycloalkyl, —(C₁-C₆alkylene)- —(C₂-C₆alkylene)-,—(C₃-C₇cycloalkylene)-, —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) and (C₃-C₇heterocycloalkyl)carbonyl portion in the abovelisted groups may be optionally substituted by one, two or three groupsR²⁵ which are independently selected in the list consisting of: C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl, —CN, OR^(D) and halo; or

R¹¹ is linked to X⁴ and is phenyl or 5- or 6-membered monocyclicheteroaryl, wherein such phenyl or 5- or 6-membered monocyclicheteroaryl is substituted by a group selected in the list consisting of:C₁-C₆ alkyl which is substituted by a group —CN; C₃-C₆ cycloalkyl whichis substituted by a group selected from: —CN, —OR^(C), —SR^(C) or halo;—N(R^(C))(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))(C₃-C₇cycloalkylene)-NR^(A)R^(B), —(C₁-C₆alkylene)-NR^(A)R^(B),—(C₃-C₇cycloalkylene)-NR^(A)R^(B), —O—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S—(C₂-C₆alkylene)-NR^(A)R^(B), —S—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-OR^(D),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—O—(C₃-C₇cycloalkylene)-OR^(D), —S—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))S(O)₂—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-OR^(D),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))S(O)₂—(C₂-C₆alkylene)-OR^(D),—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-OR^(D), —N(R^(C))S(O)₂R^(D),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl),(C₅-C₇heterocycloalkyl)(C₃-C₆cycloalkyl) and(C₃-C₇heterocycloalkyl)carbonyl, wherein any of such C₁-C₆alkyl,C₃-C₆cycloalkyl, —(C₁-C₆alkylene)- —(C₂-C₆alkylene)-,—(C₃-C₇cycloalkylene)-, —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) and (C₃-C₇heterocycloalkyl)carbonyl portion in the abovelisted groups may be optionally substituted by one, two or three groupsR²⁵ which are independently selected in the group consisting of:C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇cycloalkyl,hydroxyl, —CN, OR^(D) and halo;

R^(A) and R^(B) are at each occurrence independently —H, C₁-C₆ alkyl orC₃-C₇ cycloalkyl, such C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(D), —CN orhalo; alternatively, R^(A) and R^(B), may form together with thenitrogen atom to which they are attached an azetidine or a 4-11-memberedsaturated heterocyclic monocyclic or bicyclic ring system which isoptionally substituted by one or more group —OR^(D), —CN, halo, C₁-C₆alkyl, (C₁-C₆)hydroxyalkyl or C₃-C₇ cycloalkyl, such C₁-C₆ alkyl andC₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,C₃-C₇cycloalkyl, —OR^(D), —CN or halo; and which 6-11-membered saturatedheterocyclic monocyclic or bicyclic ring optionally contains a furtherheteroatom which is oxygen or nitrogen, said nitrogen atom optionallysubstituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein any of suchC₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionally substituted by a groupC₁-C₆ alkyl, C₃-C₇ cycloalkyl, —OR^(D), —CN, or halo; or R^(A) and R^(B)may be linked to one carbon atom of the —(C₁-C₆alkylene)-,—(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)- portion of the group linkedto the nitrogen to which they are connected to form a saturated cycle ofup to 6 ring atoms;

R^(C) is at each occurrence independently —H, C₁-C₆ alkyl,(C₁-C₄)hydroxyalkyl or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl and C₃-C₆cycloalkyl being optionally substituted by a group C₁-C₃ alkyl, —OR^(D),—CN or halo;

alternatively R^(C) may be linked to one carbon atom of the—(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)- portion of the group linkedto the nitrogen to which they are connected to form a saturated cycle ofup to 6 ring atoms

R^(D) is at each occurrence independently —H, —CH₃ or —C₂H₅;

R¹² and R¹³ are independently —H, C₁-C₆ alkyl, or halogen;

A is a divalent cycloalkylene radical having 5, 6 or 7 ring atoms; saidcycloalkylene ring being attached to W and Y and fused to a phenyl ringor to a monocyclic heteroaryl ring having 5 or 6 ring atoms, such phenylor heteroaryl ring being optionally substituted by one or two groupsR²⁴;

R²⁴ is at each occurrence independently selected from the groupconsisting of C₁-C₆ alkyl, halogen and —CN;

R² is a radical of formula (IIIb):

wherein

R¹⁷ is selected from the group consisting of lone electron pair, —H,—CF₃, —NR^(E)R^(F), —(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl), arylor heteroaryl wherein any of such —(C₃-C₇cycloalkyl),—(C₃-C₇heterocycloalkyl), aryl or heteroaryl may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl or halo; or

R¹⁷ is a group of general formula (IV)

wherein

R²⁰ is selected in the group consisting of —F, —CH₃, —C₂H₅, —CH₂OH,—CH₂OMe, —CF₂CF₃, —CH₂SCH₃, —SCH₃ and —SC₂H₅;

R²¹ is —CH₃ or —C₂H₅;

or

R²⁰ and R²¹ as defined above may form together with the carbon atom towhich they are attached a saturated 3-7-membered monocyclic ring;

R^(E) and R^(F) are each independently C₁-C₆ alkyl, optionallysubstituted by a group C₁-C₃ alkyl, —OR^(G), —CN or halo; alternativelyR^(E) and R^(F) may form together with the nitrogen atom to which theyare attached a 5-11-membered saturated monocyclic or bicyclicheterocyclic ring system which is optionally substituted by one or moregroups —OR^(G), —CN, halo, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, such C₁-C₆alkyl and C₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃alkyl, C₃-C₇cycloalkyl, —OR^(G), —CN or halo; and which 5-11-memberedsaturated monocyclic or bicyclic heterocyclic ring optionally contains afurther heteroatom which is oxygen or nitrogen, said nitrogen atomoptionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein anyof such C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionally substituted bya group C₁-C₆ alkyl or C₃-C₇ cycloalkyl;

R^(G) is —H, —CH₃ or —C₂H₅;

R¹⁸ is selected in the group consisting of aryl, heterocycloalkyl andheteroaryl, wherein any of such aryl, heterocycloalkyl or heteroaryl issubstituted by two or more groups independently selected from —CN, —OH,═O, halo, —COOR^(M), C₁-C₆ alkyl, C₃-C₆cycloalkyl, —O—(C₁-C₆alkyl),—(C₁-C₆)hydroxyalkyl, —O—(C₃-C₆cycloalkyl), —S—(C₁-C₆alkyl),—S—(C₃-C₆cycloalkyl), —NR^(H)R^(J),—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —S—(C₂-C₆alkylene)-NR^(H)R^(J),—S—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-OR^(M),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M), —N(R^(L))C(O)N(R^(H)R^(J)),—C(O)N(R^(H)R^(J)), —N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —S—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-OR^(M),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-OR^(M), —S(O)₂N(R^(H)R^(J)),—N(R^(L))S(O)₂R^(L), —N(R^(L))C(O)R^(L), OR^(L), SR^(L),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl) and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl), wherein any of suchC₁-C₆alkyl, C₃-C₆cycloalkyl, —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)-,—(C₃-C₇cycloalkylene)-, —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl) and (C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl) portion in the above listed groupsmay be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(L) or halo;

R^(H) and R^(J) are at each occurrence independently —H, C₁-C₆ alkyl orC₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), CN or halo; alternatively,R^(H) and R^(J) may also form together with the nitrogen atom to whichthey are attached a 4-11 membered saturated monocyclic or bicyclicheterocyclic ring system which is optionally substituted by one or moregroups —OR^(M), —CN, halo, NR^(O)R^(P), C₁-C₆ alkyl or C₃-C₇ cycloalkyl,such C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionally substituted by agroup C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(M), CN or halo; and which6-11-membered saturated monocyclic or bicyclic heterocyclic ringoptionally contains a further heteroatom which is oxygen or nitrogen,said nitrogen atom optionally substituted by C₁-C₆ alkyl or C₃-C₆cycloalkyl, wherein any of such C₁-C₆ alkyl or C₃-C₆ cycloalkyl may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), CN, or halo; or R^(H) and R^(J) may be linked to one carbonatom of the —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)- or—(C₃-C₇cycloalkylene)- portion of the group linked to the nitrogen towhich they are connected to form a saturated cycle of up to 6 ringatoms;

R^(L) is at each occurrence independently —H, C₁-C₆ alkyl or C₃-C₆cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), —CN or halo;

R^(M) is at each occurrence independently —H, C₁-C₆ alkyl or C₃-C₆cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group hydroxyl, —CN or halo;

R^(O) and R^(P) are each independently C₁-C₆ alkyl or C₁-C₆ cycloalkyl,optionally substituted by a group C₁-C₃ alkyl, —OR^(Q), —CN or halo;alternatively, R^(O) and R^(P) may form together with the nitrogen atomto which they are attached a 4-8-membered saturated monocyclicheterocyclic ring system which is optionally substituted by one or moregroups —OR^(Q), —CN, halo, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, and which4-8-membered saturated monocyclic heterocyclic ring optionally containsa further heteroatom which is oxygen or nitrogen, said nitrogen atomoptionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R^(Q) is —H, —CH₃ or —C₂H₅;

z¹, z², z³, and z⁴ are independently selected in the group consisting ofC, N, S, O, a group —CH— and a group —NH—, in such a combination thatthe resulting ring formed is an aromatic system;

with the proviso that when Y is a group —O(CR³R⁴)_(n)—, n is 1 and R¹⁰is —NR^(A)R^(B), —N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(A)R^(B)),—N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B) or—N(R^(C))C(O)R^(C),

then X₁ is nitrogen.

In one embodiment there is provided a compound of formula (IP), or apharmaceutically acceptable salt thereof

wherein

W is N substituted with —H, C₁-C₆ alkyl or C₃-C₅ cycloalkyl;

Y is —O(CR³R⁴)_(n)—;

R³ and R⁴ are each independently —H, —F or C₁-C₆ alkyl;

n is 0, 1, 2 or 3;

R¹ is a group (IIc)

X², X³, X⁴ and X⁵ are each independently a carbon atom, a nitrogen atom,a group —(CH)— or a group —NH—; such that each combination thereof formsan aromatic ring system;

R¹¹ is linked to X⁴ and is selected from a group consisting of:—NR^(A)R^(B), —N(R^(C))(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))(C₃-C₇cycloalkylene)-NR^(A)R^(B), —(C₁-C₆alkylene)-NR^(A)R^(B),—(C₃-C₇cycloalkylene)-NR^(A)R^(B) wherein any of such —(C₂-C₆alkylene)-and —(C₃-C₇cycloalkylene)- portion in the above listed groups may beoptionally substituted by one, two or three groups R²⁵ which areindependently selected in the list consisting of C₁-C₆ alkyl, (C₁-C₃)haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl, hydroxyl, —CN, OR^(D)and halo;

R^(A) and R^(B) may form together with the nitrogen atom to which theyare attached an azetidine or a 4-11-membered saturated heterocyclicmonocyclic ring system which is optionally substituted by one or moregroup —OR^(D), —CN, halo, C₁-C₆ alkyl, (C₁-C₆)hydroxyalkyl or C₃-C₇cycloalkyl, such C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(D), —CN orhalo; and which 6-11-membered saturated heterocyclic monocyclic orbicyclic ring optionally contains a further heteroatom which is oxygenor nitrogen, said nitrogen atom optionally substituted by C₁-C₆ alkyl orC₃-C₆ cycloalkyl, wherein any of such C₁-C₆ alkyl or C₃-C₆ cycloalkylmay be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(D), —CN, or halo; or R^(A) and R^(B) may be linked to one carbonatom of the —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)- or—(C₃-C₇cycloalkylene)- portion of the group linked to the nitrogen towhich they are connected to form a saturated cycle of up to 6 ringatoms;

R^(C) is at each occurrence independently —H, C₁-C₆ alkyl,(C₁-C₄)hydroxyalkyl or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl and C₃-C₆cycloalkyl being optionally substituted by a group C₁-C₃ alkyl, —OR^(D),—CN or halo; alternatively R^(C) may be linked to one carbon atom of the—(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)- portion of the group linkedto the nitrogen to which they are connected to form a saturated cycle ofup to 6 ring atoms;

R^(D) is at each occurrence independently —H, —CH₃ or —C₂H₅;

R¹² and R¹³ are independently —H, C₁-C₆ alkyl or halogen;

A is a divalent cycloalkylene radical having 5, 6 or 7 ring atoms; saidcycloalkylene ring being attached to W and Y, and fused to a phenyl ringor to a monocyclic heteroaryl ring having 5 or 6 ring atoms, such phenylor heteroaryl ring being optionally substituted by one or two groupsR²⁴;

R²⁴ is at each occurrence independently selected from the groupconsisting of: C₁-C₆ alkyl, halogen and —CN;

R² is a radical of formula (IIIb)

wherein

R¹⁷ is a group of general formula (IV)

wherein

R²⁰ is selected in the group consisting of —F, —CH₃, —C₂H₅, —CH₂OH,—CH₂OMe, —CF₂CF₃, —CH₂SCH₃, —SCH₃ and —SC₂H₅;

R²¹ is —CH₃ or —C₂H₅;

or

R²⁰ and R²¹ as defined above may form together with the carbon atom towhich they are attached a saturated 3-7-membered monocyclic ring;

R¹⁸ is selected in the group consisting of aryl, heterocycloalkyl andheteroaryl, wherein any of such aryl, heterocycloalkyl or heteroaryl issubstituted by two or more groups independently selected from —CN, —OH,═O, halo, —COOR^(M), C₁-C₆ alkyl, C₃-C₆cycloalkyl, —O—(C₁-C₆alkyl),—(C₁-C₆)hydroxyalkyl, —O—(C₃-C₆cycloalkyl), —NR^(H)R^(J),—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(H)R^(J)),—N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M), —(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))C(O)R^(L), OR^(L), —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) and (C₅-C₇heterocycloalkyl)-(C₃-C₆cycloalkyl), wherein any of such C₁-C₆alkyl, C₃-C₆cycloalkyl,—(C₁-C₆alkylene)-, —(C₂-C₆alkylene)-, —(C₃-C₇cycloalkylene)-,—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl) portion in the above listedgroups may be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇cycloalkyl, —OR^(L) or halo;

R^(H) and R^(J) are at each occurrence independently —H, C₁-C₆ alkyl orC₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), CN or halo; alternatively,R^(H) and R^(J) may also form together with the nitrogen atom to whichthey are attached a 4-11 membered saturated monocyclic or bicyclicheterocyclic ring system which is optionally substituted by one or moregroups —OR^(M), —CN, halo, NR^(O)R^(P), C₁-C₆ alkyl or C₃-C₇ cycloalkyl,such C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionally substituted by agroup C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(M), CN or halo; and which6-11-membered saturated monocyclic or bicyclic heterocyclic ringoptionally contains a further heteroatom which is oxygen or nitrogen,said nitrogen atom optionally substituted by C₁-C₆ alkyl or C₃-C₆cycloalkyl, wherein any of such C₁-C₆ alkyl or C₃-C₆ cycloalkyl may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), CN, or halo; or R^(H) and R^(J) may be linked to one carbonatom of the —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)- or—(C₃-C₇cycloalkylene)- portion of the group linked to the nitrogen towhich they are connected to form a saturated cycle of up to 6 ringatoms;

R^(L) is at each occurrence independently —H, C₁-C₆ alkyl or C₃-C₆cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), —CN or halo;

R^(M) is at each occurrence independently —H, C₁-C₆ alkyl or C₃-C₆cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group hydroxyl, —CN or halo;

R^(O) and R^(P) are each independently C₁-C₆ alkyl or C₁-C₆ cycloalkyl,optionally substituted by a group C₁-C₃ alkyl, —OR^(Q), —CN or halo;alternatively, R^(O) and R^(P) may form together with the nitrogen atomto which they are attached a 4-8-membered saturated monocyclicheterocyclic ring system which is optionally substituted by one or moregroups —OR^(Q), —CN, halo, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, and which4-8-membered saturated monocyclic heterocyclic ring optionally containsa further heteroatom which is oxygen or nitrogen, said nitrogen atomoptionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R^(Q) is —H, —CH₃ or —C₂H₅;

z¹, z², z³, and z⁴ are independently selected in the group consistingof: C, N, S, O, a group —CH—, and a group —NH—, in such a combinationthat the resulting ring formed is an aromatic system;

with the proviso that when Y is a group —O(CR³R⁴)_(n)—, n is 1 and R¹⁰is —NR^(A)R^(B) —N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(A)R^(B)),—N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B) or—N(R^(C))C(O)R^(C),

then X₁ is nitrogen.

In another aspect, the invention includes pharmaceutical compositionscomprising a compound of the invention, together with one or morepharmaceutically acceptable carriers and/or excipients. Particularlypreferred are compositions adapted for inhalation for pulmonaryadministration.

In another aspect, the invention includes the use of a compound of theinvention for the treatment of diseases or conditions which benefit frominhibition of p38 MAP kinase activity. The treatment of obstructive orinflammatory airways diseases is a preferred use. All forms ofobstructive or inflammatory airways diseases are potentially treatablewith the compounds of the present invention, in particular anobstructive or inflammatory airways disease that is a member selectedfrom the group consisting of chronic eosinophilic pneumonia, asthma,COPD, COPD that includes chronic bronchitis, pulmonary emphysema ordyspnea associated or not associated with COPD, COPD that ischaracterized by irreversible, progressive airways obstruction, adultrespiratory distress syndrome (ARDS), exacerbation of airwayshyper-reactivity consequent to other drug therapy and airways diseasethat is associated with pulmonary hypertension, chronic inflammatorydiseases including cystic fibrosis, bronchiectasis and pulmonaryfibrosis (Idiopathic). Efficacy is anticipated when p38 kinaseinhibitors are administered either locally to the lung (for example byinhalation and intranasal delivery) or via systemic routes (for example,oral, intravenous and subcutaneous delivery).

TERMINOLOGY

As used herein, the terms “halogen” or “halo” include fluorine,chlorine, bromine and iodine atoms.

As used herein, the term “C_(x)-C_(y)alkyl” wherein x and y areintegers, refers to a straight or branched chain alkyl radical havingfrom x to y carbon atoms. Thus when x is 1 and y is 6, for example, theterm includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein, the term “C_(x)-C_(y)haloalkyl” refers to the above“C_(x)-C_(y)alkyl” group wherein one or more hydrogen atoms are replacedby one or more halogen atoms.

As used herein, the term “C_(x)-C_(y)hydroxyalkyl” refers to the above“C_(x)-C_(y)alkyl” group wherein one hydrogen atom is replaced by onehydroxyl group.

As used herein, the term “C_(x)-C_(y)alkylene” wherein x and y areintegers, refers to a C_(x)-C_(y)alkyl radical having in total twounsatisfied valencies, such as a divalent methylene radical.

As used herein, the term “carbocyclic” refers to a mono-, bi- ortricyclic radical having up to 16 ring atoms, all of which are carbon,and includes aryl and cycloalkyl.

As used herein, the term “C_(z)-C_(k)cycloalkyl” wherein z and k areintegers refers to a monocyclic saturated carbocyclic radical havingfrom z to k carbon atoms and includes, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.Comprised within the scope of the term “C_(z)-C_(k)cycloalkyl,”, arethose radicals having two unsatisfied valencies on the same carbon atomwhich will link to any C_(x)-C_(y)alkyl, C_(x)-C_(y)alkyleneC_(z)-C_(k)cycloalkyl C_(z)-C_(k)cycloalkylene,C_(z)-C_(k)heterocycloalkyl,C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl,C_(z)-C_(k)heterocycloalkylC_(z)-C_(k)cycloalkyl or(C_(z)-C_(k))heterocycloalkylcarbonyl group by replacement of twohydrogen atoms placed on the same carbon. In such circumstances, thisradical forms a gem-disubstituted or spiro system together with theC_(x)-C_(y)alkyl, C_(x)-C_(y)alkylene C_(z)-C_(k)cycloalkylC_(z)-C_(k)cycloalkylene, C_(z)-C_(k)heterocycloalkyl,C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl,C_(z)-C_(k)heterocycloalkylC_(z)-C_(k)cycloalkyl or(C_(z)-C_(k))heterocycloalkylcarbonyl group it is linked to.

The term “C_(z)-C_(k)cycloalkylene radical” refers to aC_(z)-C_(k)cycloalkyl radical having two unsatisfied valencies ondifferent cycle carbon atoms as follows:

As used herein, the unqualified term “aryl” refers to a mono- orbi-cyclic carbocyclic aromatic radical, and includes radicals having twomonocyclic carbocyclic aromatic rings which are directly linked by acovalent bond. Illustrative of such radicals are phenyl, biphenyl andnaphthyl.

As used herein, the unqualified term “heteroaryl” refers to a mono- orbi-cyclic aromatic radical containing one or more heteroatoms selectedfrom S, N and O, and includes radicals having two such monocyclic rings,or one such monocyclic ring and one monocyclic aryl ring, which arefused through a common bond. Illustrative examples of 5,6-memberedheteroaryl are: are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, and triazinyl. Illustrative examples of 8,10-memberedheteroaryl are: benzothienyl, benzofuryl, benzimidazolyl,benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,benzotriazolyl, indolyl and indazolyl.

As used herein, the unqualified term “heterocyclyl” or “heterocyclic”and relates to a saturated mono-, bi- or tri-cyclic non-aromatic radicalcontaining one or more heteroatoms selected from S, N and O. In the caseof bicyclic heterocyclic systems, included within the scope of the termare fused, spiro and bridged bicyclic systems. In particular, the term“C_(z)-C_(k)heterocycloalkyl” refers to monocyclic(C_(z)-C_(k))cycloalkyl groups, in which at least one ring carbon atomis replaced by a heteroatom (e.g. N, NH, S or O). Examples of(C_(z)-C_(k))heterocycloalkyl include dihydropyridinyl, pyridonyl,pyrrolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, andthiomorpholinyl.

By analogy, the term “C_(z)-C_(k)heterocycloalkylene”, refers to adivalent C_(z)-C_(k)heterocycloalkyl radical, whereinC_(z)-C_(k)heterocycloalkyl is as above defined.

The term “C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl” refers to theabove “C_(x)-C_(y)alkyl” group wherein one or more hydrogen atoms arereplaced by one or more “C_(z)-C_(k)heterocycloalkyl” groups. Comprisedwithin the scope of the termC_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl” are systems where twohydrogen atoms linked to the same carbon atom in “C_(x)-C_(y)alkyl”group are replaced by one “C_(z)-C_(k)heterocycloalkyl” group. Suchradical thus form a gem-disubstituted“C_(z)-C_(k)heterocycloalkylC_(x)-C_(y)alkyl” system, such as a1,2-dimethyl-pyrrolidin-2-yl radical.

The term “C_(z)-C_(k)heterocycloalkylC_(z)-C_(k)cycloalkyl” refers tothe above “C_(z)-C_(k)cycloalkyl” group wherein one or more hydrogenatoms are replaced by one or more “C_(z)-C_(k)heterocycloalkyl” groups.

The expression “(C_(z)-C_(k))cycloalkylcarbonyl” refers to(C_(z)-C_(k))cycloalkyl-CO-groups wherein the group“(C_(z)-C_(k))cycloalkyl” has the meaning above defined.

The expression “(C_(z)-C_(k))heterocycloalkylcarbonyl” refers to(C_(z)-C_(k))heterocycloalkyl-CO— groups wherein the group“(C_(z)-C_(k))heterocycloalkyl” has the meaning above defined.

Compounds of the invention may exist in one or more geometrical,optical, enantiomeric, diastereomeric and tautomeric forms, includingbut not limited to cis- and trans-forms, E- and Z-forms, R-, S- andmeso-forms. Unless otherwise stated a reference to a particular compoundincludes all such isomeric forms, including racemic and other mixturesthereof. Where appropriate such isomers can be separated from theirmixtures by the application or adaptation of known methods (e.g.chromatographic techniques and recrystallisation techniques). Whereappropriate such isomers may be prepared by the application ofadaptation of known methods (e.g. asymmetric synthesis).

Throughout the specification the use of an asterisk “*” in thedefinition of a structural formula, indicates the point of attachmentfor the radical group to the rest of the molecule.

As used herein the term “salt” includes base addition, acid addition andammonium salts. As briefly mentioned above compounds of the inventionwhich are acidic can form salts, including pharmaceutically acceptablesalts, with bases such as alkaline metal hydroxides, e.g. sodium andpotassium hydroxides; alkaline earth metal hydroxides e.g. calcium,barium and magnesium hydroxides; with organic bases e.g.N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane,L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.Those compounds of the invention which are basic can form salts,including pharmaceutically acceptable salts with inorganic acids, e.g.with hydrohalic acids such as hydrochloric or hydrobromic acids,sulphuric acid, nitric acid or phosphoric acid and the like, and withorganic acids e.g. with acetic, formic, trifluoroacetic, tartaric,succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic,p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, andmandelic acids and the like. Those compounds (I) which have a basicnitrogen can also form quaternary ammonium salts with a pharmaceuticallyacceptable counter-ion such as ammonium, chloride, bromide, acetate,formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bissulfonate, methanesulfonate, trifluoroacetate, xinafoate, and the like.For a review on salts, see Handbook of Pharmaceutical Salts: Properties,Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002), which is incorporated herein by reference in its entirety.

It is expected that compounds of the invention may be prepared in theform of hydrates, and solvates. Any reference herein, including theclaims herein, to “compounds with which the invention is concerned” or“compounds of the invention” or “the present compounds”, and the like,includes reference to salts hydrates, and solvates of such compounds.The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Individual compounds of the invention may exist in several polymorphicforms and may be obtained in different crystal or co-crystal habits, andthey are intended to be included within the meaning of the term“compounds of the invention”.

The compounds may also be administered in the form of prodrugs thereof.Thus certain derivatives of the compounds which may be active in theirown right or may have little or no pharmacological activity themselvescan, when administered into or onto the body, be converted intocompounds of the invention having the desired activity, for example, byhydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’.Further information on the use of prodrugs may be found in Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and V.J. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press,1987 (ed. E. B. Roche, American Pharmaceutical Association; C. S. Larsenand J. Østergaard, Design and application of prodrugs, In Textbook ofDrug Design and Discovery, 3^(rd) Edition, 2002, Taylor and Francis),which are incorporated herein by reference in their entireties.

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985), which is incorporated herein by reference inits entirety. Such examples could be a prodrug of a carboxyl group (suchas —CO—O—CH₂—O—CO-tBu as used in the pivampicillin prodrug ofampicillin), an amide (—CO—NH—CH₂—NAlk₂) or an amidine(—C(═N—O—CH₃)—NH₂).

Embodiments of the Invention

It is to be understood that all preferred groups or embodimentsdescribed herebelow for compounds of formula (I) may be combined amongeach other and apply as well to compounds of formula (Ia), (Ib), (Ic),(IA), (IB), (IC) and (ID) as below defined mutatis mutandis.

In one embodiment, compounds of formula (Ia) are provided, which arecompounds of formula (I) as above defined wherein carbon stereogeniccenter on the cycloalkylene portion of ring A which is linked to group Wand identified with number (1) herebelow, possess the absoluteconfiguration herebelow represented:

In another embodiment, compounds of formula (Ib) are provided, which arecompounds of formula (I) as above defined wherein carbon stereogeniccenter on the cycloalkylene portion of ring A which are linked to groupW and Y and identified, respectively, with numbers (1) and (2)herebelow, possess the absolute configuration herebelow represented:

In a further embodiment, compound of formula (Ic) are provided, whichare compounds of formula (I) as above defined wherein carbon stereogeniccenter on the cycloalkylene portion of ring A which are linked to groupW and Y and identified, respectively, with numbers (1) and (2)herebelow, possess the absolute configuration herebelow represented:

In one embodiment, W is NH or O. In a further embodiment, W is NH.

In one embodiment, Y is a group —S(O)_(p)—, a group —O(CR³R⁴)_(n)—, agroup —(CR⁵R⁶)_(n)—, or a group —NR⁷—; p is zero and n is 0, 1 or 2. Inanother embodiment, Y is a group —S(O)_(n)— or a group —O(CR³R⁴)_(n) or;p is zero and n is 0 or 1.

In a further embodiment, Y is a group —O(CR³R⁴)_(n)— and n is 0.

In one embodiment, R³, R⁴, R⁵ and R⁶ are each independently —H, —F orC₁-C₆ alkyl. In another embodiment, R³, R⁴, R⁵ and R⁶ are —H.

In one embodiment, R⁷ is —H, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl.

In one embodiment, R⁷ is —H.

In one embodiment, A is a divalent cycloalkylene radical having 5 or 6ring atoms; said cycloalkylene ring being attached to W and Y, and fusedto a phenyl ring or to a monocyclic heteroaryl ring having 5 or 6 ringatoms, such phenyl or heteroaryl ring being optionally substituted byone or two groups R²⁴.

In a further embodiment, A is group selected in the group consisting of

In a still further embodiment, A is group

In an additional embodiment A is group

In one embodiment R²⁴ is not present or, if present, is at eachoccurrence independently selected from the group consisting of: C₁-C₂alkyl, —F, —Cl and cyano; in a further embodiment, R²⁴ is not presentor, if present, is at each occurrence independently methyl or —F. In afurther embodiment, R²⁴ is not present.

In one embodiment, R¹ is a group of formula (IIa)

In a further embodiment, R¹ is a group of formula (IIa)

and R⁸ and R⁹ form together with the nitrogen atom to which they areattached a 4-11-membered saturated monocyclic or a fused or spirobicyclic ring system optionally containing a further heteroatom which isoxygen or nitrogen, said nitrogen atom being optionally substituted byC₁-C₆ alkyl; wherein such C₁-C₆ alkyl groups may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₆ cycloalkyl, hydroxyl or halo.

In an additional embodiment, R¹ is a group of formula (IIa)

and R⁸ and R⁹ form together with the nitrogen atom to which they areattached a 4 to 7-membered saturated monocyclic ring system optionallycontaining a further heteroatom which is oxygen or nitrogen, saidnitrogen atom being optionally substituted by C₁-C₆ alkyl. In a stillfurther embodiment, such saturated monocyclic ring system is amorpholine ring.

In another embodiment, R¹ is a group of formula (IIb)

In one embodiment, X¹ is a group —(CH)— or a nitrogen atom. In anotherembodiment, X¹ is a group —(CH)—.

In one embodiment, R¹⁰ is selected from a group consisting of: —CN,—C(O)N(R^(A)R^(B)) and —N(R^(C))C(O)R^(C).

In one embodiment, R¹² is —H, C₁-C₆ alkyl or halogen.

In a further embodiment, R¹ is a group of formula (IIb)

wherein X¹ is a group —(CH)—, R¹⁰ is selected from a group consisting of—CN, —C(O)N(R^(A)R^(B)), and —N(R^(C))C(O)R^(C); and R¹² is —H.

In a further embodiment, R¹ is a group of formula (IIc)

In one embodiment, the group (IIc) is a group of formula (IIca) or(IIcb) which is connected to the group Y through one of the carbons asbelow indicated

In another embodiment, the group (IIc) is a group of formula (IIca) asabove defined which is connected to the group Y through the carbonadjacent to X₂

In one embodiment, X⁴ is a carbon atom.

In one embodiment, X⁵ is a nitrogen atom.

In another embodiment, X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ isa nitrogen atom and X² is nitrogen.

In another embodiment, X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ isa nitrogen atom and X² is group —CH—.

In another embodiment, X⁴ is a nitrogen atom, X⁵ is a group —CH— atom,X³ is a carbon atom and X² is a group —CH—.

In one embodiment, R¹³ is —H, C₁-C₆ alkyl or halogen.

In a further embodiment, the group (IIc) is a group of formula (IIca) asabove defined which is connected to the group Y through the carbonadjacent to X₂

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H.

In one embodiment, R¹ is selected from a group consisting of—NR^(A)R^(B), (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl),—(C₃-C₇heterocycloalkyl), wherein any of such(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) or —(C₃-C₇heterocycloalkyl) may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,hydroxyl or halo.

In another embodiment, R¹¹ is selected from a group consisting of—NR^(A)R^(B), —(C₁-C₆alkylene)-NR^(A)R^(B),(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl), —(C₃-C₇heterocycloalkyl), whereinany of such (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) or—(C₃-C₇heterocycloalkyl) may be optionally substituted by one, two orthree groups R²⁵ which are independently selected in the list consistingof C₁-C₆ alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇cycloalkyl, hydroxyl, —CN, OR^(D) and halo.

In another embodiment, R¹¹ is phenyl or 5- or 6-membered monocyclicheteroaryl which is substituted by (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl)or —(C₃-C₇heterocycloalkyl), wherein any of such(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) or —(C₃-C₇heterocycloalkyl) may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,hydroxyl or halo.

In another embodiment, R²⁵ is phenyl or 5- or 6-membered monocyclicheteroaryl which is substituted by (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl)or —(C₃-C₇heterocycloalkyl), wherein any of such(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) or —(C₃-C₇heterocycloalkyl) may beoptionally substituted by one, two or three groups R²⁵ which areindependently selected in the list consisting of C₁-C₆ alkyl, (C₁-C₃)haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl, hydroxyl and halo.

In one embodiment, R²⁵ is one, two or three groups independentlyselected in the list consisting of C₁-C₆ alkyl, (C₁-C₃) haloalkyl,(C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl, hydroxyl, —CN, OR^(D) and halo.

In one embodiment, R^(A) and R^(B) are at each occurrence independentlyC₁-C₆ alkyl or C₃-C₇ cycloalkyl, such C₁-C₆ alkyl and C₃-C₇ cycloalkylbeing optionally substituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl,OR^(D), CN or halo.

In another embodiment, R^(A) and R^(B) form together with the nitrogenatom to which they are attached an azetidine or a 4-11-memberedsaturated monocyclic or bicyclic heterocyclic ring system which isoptionally substituted by one or more groups —OR^(D), CN, halo, C₁-C₆alkyl, (C₁-C₆)hydroxyalkyl or C₃-C₇ cycloalkyl, such C₁-C₆ alkyl andC₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,C₃-C₇cycloalkyl —OR^(D), —CN or halo.

In a still further embodiment R^(A) and R^(B) form together with thenitrogen atom to which they are attached an azetidine or a 4-11-memberedsaturated monocyclic or bicyclic heterocyclic ring system which isoptionally substituted by one or more groups —OR^(D), —CN, halo, C₁-C₆alkyl, (C₁-C₆)hydroxyalkyl or C₃-C₇ cycloalkyl, such C₁-C₆ alkyl,(C₁-C₆)hydroxyalkyl and C₃-C₇ cycloalkyl being optionally substituted bya group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(D), —CN or halo; and which6-11-membered saturated monocyclic or bicyclic heterocyclic ringcontains a further heteroatom which is oxygen or nitrogen, said nitrogenatom optionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, whereinany of such C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, OR^(D), CN orhalo.

In one embodiment, R¹¹ is a group

wherein R²⁵ is optionally present and represents one, two or threesubstituents independently selected in the list consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl, —CN, OR^(D) and halo; and wherein the asterisk represents thepoint of attachment for group R¹¹ to the rest of the molecule via X⁴.

In one embodiment, R¹¹ is a group

wherein R²⁵ is optionally present and represents one, two or threesubstituents independently selected in the list consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl, —CN, OR^(D) and halo; and wherein the asterisk represents thepoint of attachment for group R¹¹ to the rest of the molecule via X⁴.

In further embodiment, R¹¹ is a group

wherein R²⁵ represents one or two C₁-C₆ alkyl substituents and whereinthe asterisk represents the point of attachment for group R¹¹ to therest of the molecule via X⁴.

In one embodiment, R¹¹ is a group

wherein R²⁵ is optionally present and represents one, two or threesubstituents independently selected in the list consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl, —CN, OR^(D) and halo; and wherein the asterisk represents thepoint of attachment for group R¹¹ to the rest of the molecule via X⁴.

In a further embodiment, R¹¹ is a group

wherein R²⁵ represents one, two or three substituents independentlyselected in the list consisting of C₁-C₆ alkyl, (C₁-C₃) haloalkyl,(C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl, hydroxyl, —CN, OR^(D) and haloand wherein the asterisk represents the point of attachment for groupR¹¹ to the rest of the molecule via X⁴.

In a still further embodiment, R¹¹ is a group

wherein R²⁵ represents one, two or three substituents independentlyselected in the list consisting of C₁-C₆ alkyl, (C₁-C₃) haloalkyl,(C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl, hydroxyl, —CN, OR^(D) and haloand wherein the asterisk represents the point of attachment for groupR¹¹ to the rest of the molecule via X⁴.

In a further embodiment, R¹¹ is a group

wherein R²⁵ represents independently one or two C₁-C₆ alkyl substituentsand wherein the asterisk represents the point of attachment for groupR¹¹ to the rest of the molecule via X⁴.

In a further embodiment, R¹¹ is a group

wherein the asterisk represents the point of attachment for group R¹¹ tothe rest of the molecule via X⁴.

In a further embodiment, R¹¹ is a group

wherein the asterisk represents the point of attachment for group R¹¹ tothe rest of the molecule via X⁴.

In a still further embodiment, R¹¹ is a group

wherein the asterisk represents the point of attachment for group R¹¹ tothe rest of the molecule via X⁴.

In a still further embodiment R¹¹ is a group

wherein the asterisk represents the point of attachment for group R¹¹ tothe rest of the molecule via X⁴.

In a still further embodiment, R¹¹ is a group

wherein the asterisk represents the point of attachment for group R¹¹ tothe rest of the molecule via X⁴.

In a still further embodiment, R¹¹ is a group

wherein the asterisk represents the point of attachment for group R¹¹ tothe rest of the molecule via X⁴.

In another embodiment, R² is a radical of formula (IIIb)

In one embodiment R¹⁷ is selected from the group consisting of loneelectron pair, —H, —CF₃, —NR^(E)R^(F), —(C₃-C₆cycloalkyl),—(C₄-C₆heterocycloalkyl), aryl or heteroaryl wherein any of such—(C₃-C₆cycloalkyl), —(C₄-C₆heterocycloalkyl), aryl or heteroaryl may beoptionally substituted by a group methyl, isopropyl or halo. In anotherembodiment, R¹⁷ is selected from the group consisting of lone electronpair, —H, —CF₃, morpholine, cyclohexyl, phenyl or pyridyl.

In another embodiment, R¹⁷ is a group of general formula (IV)

In one embodiment, R²⁰ is selected in the group consisting of F, —CH₃;—CH₂OH, —CH₂OMe, —CH₂SCH₃; in another embodiment, R²⁰ is selected in thegroup consisting of —CH₃; —CH₂OH, —CH₂OMe. In another embodiment, R²⁰ is—CH₃.

In one embodiment, R^(2′) is —CH₃.

In another embodiment R²⁰ and R²¹ are —CH₃.

In another embodiment, R²⁰ and R²¹ as defined above may form togetherwith the carbon atom to which they are attached a cyclohexane orcyclopropyl ring; in a further embodiment, R²⁰ and R²¹ as defined abovemay form together with the carbon atom to which they are attached acyclopropyl ring.

In one embodiment R¹⁸ is phenyl, heterocycloalkyl or heteroaryl whereinany of such phenyl, heterocycloalkyl or heteroaryl is substituted by twoor more groups independently selected from —CN, —OH, ═O, halo,—COOR^(M), C₁-C₆alkyl, C₃-C₆cycloalkyl, —O—(C₁-C₆alkyl),—O—(C₃-C₆cycloalkyl), —S—(C₁-C₆alkyl), —S—(C₃-C₆cycloalkyl),—NR^(H)R^(J), —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —S—(C₂-C₆alkylene)-NR^(H)R^(J),—S—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-OR^(M),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M), —N(R^(L))C(O)N(R^(H)R^(J)),—C(O)N(R^(H)R^(J)), —N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —S—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-OR^(M),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-OR^(M), —S(O)₂N(R^(H)R^(J)),—N(R^(L))S(O)₂R^(L), —N(R^(L))C(O)R^(L), OR^(L), SR^(L),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl) and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl), wherein any of such alkyl,cycloalkyl, alkylene, cycloalkylene, heterocycloalkyl,heterocycloalkyl-(C₁-C₆ alkyl), heterocycloalkyl)-(C₃-C₆ cycloalkyl) andheterocycloalkylcarbonyl portion in the above listed groups may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, —OR^(L)or halo.

In one embodiment R^(H) and R^(J) are independently —H, C₁-C₆ alkyl orC₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), CN or halo; alternatively,R^(H) and R^(J) may also form together with the nitrogen atom to whichthey are attached a 4-11 membered saturated monocyclic or bicyclicheterocyclic ring system which is optionally substituted by one or moregroups —OR^(M), —CN, halo, NR^(O)R^(P), C₁-C₆ alkyl or C₃-C₇ cycloalkyl,such C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionally substituted by agroup C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(M), CN or halo; and which6-11-membered saturated monocyclic or bicyclic heterocyclic ringoptionally contains a further heteroatom which is oxygen or nitrogen,said nitrogen atom optionally substituted by C₁-C₆ alkyl or C₃-C₆cycloalkyl, wherein any of such C₁-C₆ alkyl or C₃-C₆ cycloalkyl may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), CN or halo; or R^(H) and R^(J) may be linked to one carbon atomof the —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)-portion of the group linked to the nitrogen to which they are connectedto form a saturated cycle of up to 6 ring atoms.

In a further embodiment R^(H) and R^(J) are independently —H, C₁-C₆alkyl or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl beingoptionally substituted by a group C₁-C₃ alkyl, —OR^(M), CN or halo;alternatively, R^(H) and R^(J) may also form together with the nitrogenatom to which they are attached a 4-7 membered saturated monocyclicheterocyclic ring system which is optionally substituted by one or moregroups halo, NR^(O)R^(P) or C₁-C₆ alkyl, such C₁-C₆ alkyl beingoptionally substituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(M),CN or halo; and which 6-7-membered saturated monocyclic heterocyclicring optionally contains a further heteroatom which is oxygen ornitrogen, said nitrogen atom optionally substituted by C₁-C₆ alkyl orC₃-C₆ cycloalkyl, wherein any of such C₁-C₆ alkyl or C₃-C₆ cycloalkylmay be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(M), CN, or halo; or R^(H) and R^(J) may be linked to one carbonatom of the —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)- or—(C₃-C₇cycloalkylene)-portion of the group linked to the nitrogen towhich they are connected to form a saturated cycle of up to 6 ringatoms.

In another embodiment, R^(L) is at each occurrence independently —H,C₁-C₆ alkyl or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkylbeing optionally substituted by a group C₁-C₃ alkyl, —OR^(M), —CN orhalo; R^(M) is at each occurrence independently —H, C₁-C₆ alkyl or C₃-C₆cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group hydroxyl, —CN or halo; R^(O) and R^(P) are eachindependently C₁-C₆ alkyl or C₁-C₆ cycloalkyl, optionally substituted bya group C₁-C₃ alkyl, —OR^(Q), —CN or halo; alternatively, R^(O) andR^(P) may form together with the nitrogen atom to which they areattached a 4-8-membered saturated monocyclic heterocyclic ring systemwhich is optionally substituted by one or more groups —OR^(Q), —CN,halo, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, and which 4-8-membered saturatedmonocyclic heterocyclic ring optionally contains a further heteroatomwhich is oxygen or nitrogen, said nitrogen atom optionally substitutedby C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R^(Q) is —H, —CH₃ or —C₂H₅.

In one embodiment, z¹=—CH—, z²=C, z³ and z⁴ are N; in anotherembodiment, z¹=O, z²=C, z³ and z⁴ are N; in a further embodiment,z¹=—CH—, z² and z³ are N and z⁴ is —CH—; in an additional embodiment,z¹=N, z² is C, z³ is N and z⁴ is O; in a still further embodiment, z¹=N,z² is C, z³ is O and z⁴ is N.

In a further embodiment, R² is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ is —CH₃ or —CH₂OH, and R²¹ is —CH₃.

In another embodiment R² is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ and R²¹ are —CH₃ and wherein R¹⁸ is phenyl substituted bytwo or more groups independently selected from —CN, —OH, halo,—COOR^(M), C₁-C₆alkyl, —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—(C₁-C₆alkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —S—(C₂-C₆alkylene)-OR^(M),(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl), and (C₅-C₇heterocycloalkyl)-(C₃-C₆cycloalkyl) wherein any of such C₁-C₆alkyl, —(C₁-C₆alkylene)-,—(C₂-C₆alkylene), (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) and(C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl) may be optionally substitutedby a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, OR^(L) or halo; wherein R^(H)and R^(J) are independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), CN or halo; alternatively,R^(H) and R^(J) may also form together with the nitrogen atom to whichthey are attached a 4-11 membered saturated monocyclic heterocyclic ringsystem which is optionally substituted by one or more groups —OR^(M),—CN, halo, NR^(O)R^(P), C₁-C₆ alkyl or C₃-C₇ cycloalkyl, such C₁-C₆alkyl and C₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃alkyl, C₃-C₇cycloalkyl, —OR^(M), CN or halo; and which 6-11-memberedsaturated monocyclic or bicyclic heterocyclic ring optionally contains afurther heteroatom which is oxygen or nitrogen, said nitrogen atomoptionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein anyof such C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionally substituted bya group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, —OR^(M), CN, or halo; or R^(H)and R^(J) may be linked to one carbon atom of the —(C₁-C₆alkylene)-,—(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)-portion of the group linkedto the nitrogen to which they are connected to form a saturated cycle ofup to 6 ring atoms; wherein R^(L) is at each occurrence independently—H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆cycloalkyl being optionally substituted by a group C₁-C₃ alkyl, —OR^(M),—CN or halo; and wherein R^(M) is at each occurrence independently —H,C₁-C₆ alkyl or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkylbeing optionally substituted by a group hydroxyl, —CN or halo.

In an additional embodiment R² is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is phenyl substituted by two ormore groups independently selected from halo, —OH, C₁-C₆ alkyl,—O—(C₂-C₆alkylene)-NR^(H)R^(J) and —(C₁-C₆alkylene)-NR^(H)R^(J).

In another embodiment R² is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is a 5 or 6-membered heteroarylwhich is substituted by two or more groups independently selected fromC₁-C₆alkyl, —(C₁-C₆)hydroxyalkyl, —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J)and —(C₁-C₆alkylene)-NR^(H)R^(J) wherein any of such C₁-C₆alkyl,—(C₁-C₆)hydroxyalkyl, —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)-,(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) and (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) portion in the above listed groups may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl OR^(L) or halo.

In another embodiment, R² is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is a heterocycloalkyl which issubstituted by two or more groups independently selected from ═O,C₁-C₆alkyl, —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J) and—(C₁-C₆alkylene)-NR^(H)R^(J) wherein any of such C₁-C₆alkyl and—(C₁-C₆alkylene)-portion in the above listed groups may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl OR^(L) or halo.

In one embodiment, compounds of formula (IA) are provided wherein W isNH, Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group

wherein R¹ is a group of formula (IIca) as above defined which isconnected to the group Y through the carbon adjacent to X²

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H; wherein R¹¹ is a group:

wherein R²⁵ is optionally present and represents one, two or threesubstituents independently selected in the list consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl and halo; and wherein the asterisk represents the point ofattachment for group R¹¹ to the rest of the molecule via X⁴; wherein R²is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ and R²¹ are —CH₃ and wherein R¹⁸ is aryl substituted by twoor more groups independently selected from —CN, —OH, halo, —COOR^(M),C₁-C₆alkyl, —O—(C₁-C₆alkyl), —(C₁-C₆)hydroxyalkyl,—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl) and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl) wherein any of suchC₁-C₆alkyl, —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)-,(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) and (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) portion may be optionally substituted by a group C₁-C₆alkyl, C₃-C₇ cycloalkyl, OR^(L) or halo; wherein R^(H) and R^(J) areindependently —H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, such C₁-C₆ alkyl orC₃-C₆ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,—OR^(M), CN or halo; or R^(H) and R^(J) may form together with thenitrogen atom to which they are attached a 4-11 membered saturatedmonocyclic or bicyclic heterocyclic ring system which is optionallysubstituted by one or more C₁-C₆alkyl and which 4-1-membered saturatedmonocyclic or bicyclic heterocyclic ring optionally contain a furtherheteroatom which is oxygen or nitrogen and R^(M) is —H.

In one embodiment, compounds of formula (IB) are provided wherein W isNH, Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group:

wherein R¹ is a group of formula (IIca) as above defined which isconnected to the group Y through the carbon adjacent to X²

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H;

R¹¹ is a group

wherein R²⁵ is optionally present and represents one, two or threesubstituents independently selected in the list consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl,

(C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl, hydroxyl and halo; and whereinthe asterisk represents the point of attachment for group R¹¹ to therest of the molecule via X⁴; R² is a radical of formula (IIIb):

wherein z¹=—CH—, z²C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is a phenyl substituted by two ormore groups independently selected from —OH, halo, C₁-C₆alkyl,—(C₁-C₆)hydroxyalkyl, —O—(C₂-C₆alkylene)-NR^(H)R^(J) or—(C₁-C₆alkylene)-NR^(H)R^(J), wherein any of such C₁-C₆alkyl,—(C₁-C₆alkylene)- and —(C₂-C₆alkylene)- portion may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, OR^(L) or halo;wherein R^(H) and R^(J) are independently —H, C₁-C₆ alkyl or C₃-C₆cycloalkyl, such C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), CN or halo; or R^(H) andR^(J) may form together with the nitrogen atom to which they areattached a 4-11 membered saturated monocyclic or bicyclic heterocyclicring system which is optionally substituted by one or more C₁-C₆alkyland which 4-11 membered saturated monocyclic or bicyclic heterocyclicring optionally contain a further heteroatom which is oxygen or nitrogenand R^(M) is —H.

In one embodiment, compounds of formula (IC) are provided wherein W isNH, Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group

R¹ is a group of formula (IIca) as above defined which is connected tothe group Y through the carbon adjacent to X₂

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H; wherein R¹¹ is a group

wherein R²⁵ is optionally present and represents one two or threesubstituents independently selected in the list consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl and halo; and wherein the asterisk represents the point ofattachment for group R¹¹ to the rest of the molecule via X⁴; wherein R²is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is a 5 or 6-membered heteroarylwhich is substituted by two or more groups independently selected fromC₁-C₆alkyl, —(C₁-C₆)hydroxyalkyl, —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J)and —(C₁-C₆alkylene)-NR^(H)R^(J), wherein any of such C₁-C₆alkyl,—(C₁-C₆alkylene)- and —(C₂-C₆alkylene)- portion in the above listedgroups may be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇cycloalkyl OR^(L) or halo.

In one embodiment, compounds of formula (ID) are provided wherein W isNH, Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group

wherein R¹ is a group of formula (IIca) as above defined which isconnected to the group Y through the carbon adjacent to X₂

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H;

wherein R¹¹ is a group

wherein R²⁵ is optionally present and represents one two or threesubstituents independently selected in the list consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl and halo; and wherein the asterisk represents the point ofattachment for group R¹¹ to the rest of the molecule via X⁴; wherein R²is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of generalformula (IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is a heterocycloalkyl substitutedby two or more groups independently selected from ═O, C₁-C₆alkyl,—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J) or —(C₁-C₆alkylene)-NR^(H)R^(J),wherein any of such C₁-C₆alkyl and —(C₁-C₆alkylene)-portion in the abovelisted groups may be optionally substituted by a group C₁-C₆ alkyl,C₃-C₇ cycloalkyl OR^(L) or halo.

In one embodiment, a compound of formula (I) is selected from the groupconsisting of:

-   1-[5-tert-Butyl-2-(2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}urea;-   1-[5-tert-Butyl-2-(2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}urea    formate salt;-   1-{5-tert-Butyl-2-[5-(2-dimethylamino-ethoxy)-2-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[5-(2-dimethylamino-ethoxy)-2-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(4-chloro-3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-methyl-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea    formate salt;-   1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-4-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[3-chloro-5-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea    formate salt;-   1-[5-tert-Butyl-2-(3-chloro-5-piperidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[3-chloro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[2-chloro-5-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea    formate salt;-   1-[5-tert-Butyl-2-(3-fluoro-5-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[3-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-5-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(3-fluoro-5-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[3-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-5-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{((1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-cyano-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea    formate salt;-   1-(5-tert-Butyl-2-{4-chloro-3-[2-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-{((1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-(5-tert-Butyl-2-{4-chloro-3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-(5-tert-Butyl-2-{4-fluoro-3-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{2-[3-(2-Azetidin-1-yl-ethyl)-4-fluoro-phenyl]-5-tert-butyl-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-(5-tert-Butyl-2-{3-[2-(3-dimethylamino-azetidin-1-yl)-ethyl]-4-fluoro-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethyl)-4-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(4-chloro-3-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(4-chloro-3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(4-chloro-3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(4-fluoro-3-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-fluoro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(4-fluoro-3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-hydroxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl}-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(3-hydroxy-5-methyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-4-hydroxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-hydroxymethyl-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea    formate salt;-   1-(5-tert-Butyl-2-{4-hydroxymethyl-3-[2-(4-methyl-piperazin-1H-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-4-hydroxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-{5-tert-Butyl-2-[4-hydroxymethyl-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea    formate salt;-   1-(5-tert-Butyl-2-{4-hydroxymethyl-3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   -{5-tert-Butyl-2-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(3-chloro-5-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(3-chloro-5-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-[1,4]oxazepan-4-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(4-chloro-3-piperidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(4-chloro-3-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[1-(2-dimethylamino-ethyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(piperidin-4-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-((R)-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-((S)-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-((R)-1-methyl-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-((S)-1-methyl-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-3′-hydroxymethyl-1′H-[1,4′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(3-morpholin-4-yl-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(3-morpholin-4-yl-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((R)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea    formate salt;-   1-[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl})-urea;-   1-[5-tert-Butyl-2-(2,5-dimethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-[5-tert-Butyl-2-(4-chloro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(2,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;-   1-{5-tert-Butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-{5-tert-Butyl-2-[4-methyl-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[5-tert-Butyl-2-(3-chloro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;-   1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-4′-hydroxymethyl-1′H-[1,3′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl)}-urea;-   1-[5-tert-Butyl-2-(3,5-dimethyl-isoxazol-4-yl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea-   and pharmaceutically acceptable salts thereof.

Utility.

As mentioned above the compounds of the invention are p38MAPKinhibitors, and thus may have utility for the treatment of diseases orconditions which benefit from inhibition of the p38 enzyme. Suchdiseases and conditions are known from the literature and several havebeen mentioned above. However, the compounds are generally of use asanti-inflammatory agents, particularly for use in the treatment ofrespiratory disease In particular, the compounds may be used in thetreatment of chronic obstructive pulmonary disease (COPD), chronicbronchitis, lung fibrosis, pneumonia, acute respiratory distresssyndrome (ARDS), pulmonary emphysema, or smoking-induced emphysema,intrinsic (non-allergic asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, steroid resistant asthma,neutrophilic asthma, bronchitic asthma, exercise induced asthma,occupational asthma and asthma induced following bacterial infection,cystic fibrosis, pulmonary fibrosis and bronchiectasis.

The present invention provides the use of the compounds of the inventionfor the prevention and/or treatment of any disease or condition whichbenefit from inhibition of the p38 enzyme.

In a further aspect the present invention provides the use of compoundsof the invention for the preparation of a medicament for the preventionand/or treatment of any disease or condition which benefit frominhibition of the p38 enzyme.

Moreover the present invention provides a method for prevention and/ortreatment of any disease which benefit from inhibition of the p38enzyme, said method comprises administering to a patient in need of suchtreatment a therapeutically effective amount of a compound of theinvention.

Compositions.

As mentioned above, the compounds with which the invention is concernedare p38 kinase inhibitors, and are useful in the treatment of severaldiseases for example inflammatory diseases of the respiratory tract.Examples of such diseases are referred to above, and include asthma,rhinitis, allergic airway syndrome, bronchitis and chronic obstructivepulmonary disease.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing treatment. Optimum dose levels and frequency of dosing willbe determined by clinical trial, as is required in the pharmaceuticalart. In general, the daily dose range for oral administration will liewithin the range of from about 0.001 mg to about 100 mg per kg bodyweight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1to 10 mg per kg, in single or divided doses. In general, the daily doserange for inhaled administration will lie within the range of from about0.1 μg to about 1 mg per kg body weight of a human, preferably 0.1 μg to50 μg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases. For thepurpose of the invention, inhaled administration is preferred.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. Orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations, such as oral, topical, or sterile parenteral solutions orsuspensions. Tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or coloring agents.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

However, for treatment of an inflammatory disease of the respiratorytract, compounds of the invention may also be formulated for inhalation,for example as a nasal spray, or dry powder or aerosol inhalers. Fordelivery by inhalation, the active compound is preferably in the form ofmicroparticles. They may be prepared by a variety of techniques,including spray-drying, freeze-drying and micronisation. Aerosolgeneration can be carried out using, for example, pressure-driven jetatomizers or ultrasonic atomizers, preferably using propellant-drivenmetered aerosols or propellant-free administration of micronized activecompounds from, for example, inhalation capsules or other “dry powder”delivery systems.

By way of example, a composition of the invention may be prepared as asuspension for delivery from a nebuliser or as an aerosol in a liquidpropellant, for example for use in a pressurised metered dose inhaler(PMDI). Propellants suitable for use in a PMDI are known to the skilledperson, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl₂F₂) andHFA-152 (CH₄F₂ and isobutane).

In a preferred embodiment of the invention, a composition of theinvention is in dry powder form, for delivery using a dry powder inhaler(DPI). Many types of DPI are known.

Microparticles for delivery by administration may be formulated withexcipients that aid delivery and release. For example, in a dry powderformulation, microparticles may be formulated with large carrierparticles that aid flow from the DPI into the lung. Suitable carrierparticles are known, and include lactose particles; they may have a massmedian aerodynamic diameter of greater than 90 μm.

In the case of an aerosol-based formulation, an example is:

Compound of the invention   24 mg/canister Lecithin, NF Liq. Conc.  1.2mg/canister Trichlorofluoromethane, NF 4.025 g/canisterDichlorodifluoromethane, NF 12.15 g/canister.

The active compounds may be dosed as described depending on the inhalersystem used. In addition to the active compounds, the administrationforms may additionally contain excipients, such as, for example,propellants (e.g. Frigen in the case of metered aerosols),surface-active substances, emulsifiers, stabilizers, preservatives,flavorings, fillers (e.g. lactose in the case of powder inhalers) or, ifappropriate, further active compounds.

For the purposes of inhalation, a large number of systems are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g. Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inparticular in the case of powder inhalers, a number of technicalsolutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or theinhalers for example as described EP-A-0505321, which is incorporatedherein by reference in its entirety). Additionally, compounds of theinvention may be delivered in multi-chamber devices thus allowing fordelivery of combination agents.

Combinations.

Other compounds may be combined with compounds with which the inventionis concerned for the prevention and treatment of inflammatory diseases,in particular respiratory diseases. Thus the present invention is alsoconcerned with pharmaceutical compositions comprising a therapeuticallyeffective amount of a compound of the invention and one or more othertherapeutic agents. Suitable therapeutic agents for a combinationtherapy with compounds of the invention include, but are not limited to:(1) corticosteroids, such as fluticasone propionate, fluticasonefuroate, mometasone furoate, beclometasone dipropionate, ciclesonide,budesonide, GSK 685698, GSK 870086, QAE 397, QMF 149, TPI-1020; (2)P2-adrenoreceptor agonists such as salbutamol, albuterol, terbutaline,fenoterol, and long acting P2-adrenoreceptor agonists such assalmeterol, indacaterol, formoterol (including formoterol fumarate),arformoterol, carmoterol, GSK 642444, GSK 159797, GSK 159802, GSK597501, GSK 678007, AZD3199, vilanterol, olodaterol and abediterol; (3)corticosteroid/long acting 32 agonist combination products such assalmeterol/fluticasone propionate (Advair/Seretide),formoterol/budesonide (Symbicort), formoterol/fluticasone propionate(Flutiform), formoterol/ciclesonide, formoterol/mometasone furoate,formoterol/beclometasone dipropionate, indacaterol/mometasone furoate,Indacaterol/QAE 397, GSK 159797/GSK 685698, GSK 159802/GSK 685698, GSK642444/GSK 685698, GSK 159797/GSK 870086, GSK 159802/GSK 870086, GSK642444/GSK 870086, arformoterol/ciclesonide; (4) anticholinergic agents,for example muscarinic-3 (M3) receptor antagonists such as ipratropiumbromide, tiotropium bromide, Aclidinium (LAS-34273), NVA-237, GSK233705, Darotropium, GSK 573719, GSK 961081, QAT 370, QAX 028, EP-101;(5) dual pharmacology M3-anticholinergic/β2-adrenoreceptor agonists suchas GSK961081, AZD2115 and LAS 190792; (6) leukotriene modulators, forexample leukotriene antagonists such as montelukast, zafirulast orpranlukast or leukotriene biosynthesis inhibitors such as Zileuton orBAY-1005, or LTB4 antagonists such as Amelubant, or FLAP inhibitors suchas GSK 2190914, AM-103; (7) phosphodiesterase-IV (PDE-IV) inhibitors(oral or inhaled), such as roflumilast, cilomilast, Oglemilast,ONO-6126, Tetomilast, Tofimilast, UK 500,001, GSK 256066; (8)antihistamines, for example selective histamine-1 (H1) receptorantagonists, such as fexofenadine, citirizine, loratidine or astemizoleor dual H1/H3 receptor antagonists such as GSK 835726, GSK 1004723, orselective histamine-4 (H4) receptor antagonists, such as ZPL3893787; (9)antitussive agents, such as codeine or dextramorphan; (10) a mucolytic,for example N acetyl cysteine or fudostein; (11) aexpectorant/mucokinetic modulator, for example ambroxol, hypertonicsolutions (e.g. saline or mannitol) or surfactant; (12) a peptidemucolytic, for example recombinant human deoxyribonoclease I(dornase-alfa and rhDNase) or helicidin; (13) antibiotics, for exampleazithromycin, tobramycin and aztreonam; (14) non-selective COX-1/COX-2inhibitors, such as ibuprofen or ketoprofen; (15) COX-2 inhibitors, suchas celecoxib and rofecoxib; (16) VLA-4 antagonists, such as thosedescribed in WO97/03094 and WO97/02289, which are incorporated herein byreference in their entireties; (17) TACE inhibitors and TNF-αinhibitors, for example anti-TNF monoclonal antibodies, such as Remicadeand CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel;(18) inhibitors of matrix metalloprotease, for example MMP-12; (19)human neutrophil elastase inhibitors, such as ONO-6818 or thosedescribed in WO2005/026124, WO2003/053930 and WO06/082412, which areincorporated herein by reference in their entireties; (20) A2bantagonists such as those described in WO2002/42298, which isincorporated herein by reference in its entirety; (21) modulators ofchemokine receptor function, for example antagonists of CCR3 and CCR8;(22) compounds which modulate the action of other prostanoid receptors,for example a thromboxane A₂ antagonist; DPI antagonists such asMK-0524, CRTH2 antagonists such as ODC9101 and OC000459 and AZD1981 andmixed DPI/CRTH2 antagonists such as AMG 009 and AMG853; (23) PPARagonists including PPAR alpha agonists (such as fenofibrate), PPAR deltaagonists, PPAR gamma agonists such as Pioglitazone, Rosiglitazone andBalaglitazone; (24) methylxanthines such as theophylline oraminophylline and methylxanthine/corticosteroid combinations such astheophylline/budesonide, theophylline/fluticasone propionate,theophylline/ciclesonide, theophylline/mometasone furoate andtheophylline/beclometasone dipropionate; (25) A2a agonists such as thosedescribed in EP1052264 and EP1241176, which are incorporated herein byreference in their entireties; (26) CXCR2 or IL-8 antagonists such asSCH 527123 or GSK 656933; (27) IL-R signalling modulators such askineret and ACZ 885; (28) MCP-1 antagonists such as ABN-912.

The invention is also directed to a kit comprising the pharmaceuticalcompositions of compounds of the invention alone or in combination withor in admixture with one or more pharmaceutically acceptable carriersand/or excipients and a device which may be a single- or multi-dose drypowder inhaler, a metered dose inhaler or a nebulizer.

Methods of Synthesis.

In one aspect of the present invention, a process for the preparation ofcompounds of the invention is provided, according to general syntheticroutes described in this section. In the following reaction schemes,unless otherwise indicated, the groups mentioned assume the same meaningas those reported for compounds of formula (I).

The skilled person may introduce, where appropriate, suitable variationsto the conditions specifically described in the experimentals in orderto adapt the synthetic routes to the provision of further compounds ofthe invention. Such variations may include, but are not limited to, useof appropriate starting materials to generate different compounds,changes in the solvent and temperature of reactions, replacements ofreactives with analogous chemical role, introduction or removal ofprotection/deprotection stages of functional groups sensitive toreaction conditions and reagents, as well as introduction or removal ofspecific synthetic steps oriented to further functionalisation of thechemical scaffold.

Processes which can be used and are described and reported in Examplesand Schemes, should not be viewed as limiting the scope of the syntheticmethods available for the preparation of the compounds of the invention.

The process described is particularly advantageous as it is susceptibleof being properly modulated, through any proper variant known to theskilled person, so as to obtained any of the desired compounds of theinvention. Such variants are comprised within the scope of the presentinvention.

From all of the above, it should be clear to the skilled person that anyof the described groups may be present as such or in any properlyprotected form.

In particular, functional groups present in the intermediate andcompounds and which could generate unwanted side reaction andby-products, need to be properly protected before the alkylation,acylation, coupling or sulfonylation takes place. Likewise, subsequentdeprotection of those same protected groups may follow upon completionof the said reactions.

In the present invention, unless otherwise indicated, the term“protecting group” designates a protective group adapted to preserve thefunction of the group it is bound to. Typically, protective groups areused to preserve amino, hydroxyl, or carboxyl functions. Appropriateprotecting groups may thus include, for example, benzyl,benzyloxycarbonyl, t-butoxycarbonyl, alkyl or benzyl esters or the like,which are well known to those skilled in the art [see, for a generalreference, T. W. Green; Protective Groups in Organic Synthesis (Wiley,N. Y. 1981), which is incorporated herein by reference in its entirety].

Likewise, selective protection and deprotection of any of the saidgroups, for instance including carbonyl, hydroxyl or amino groups, maybe accomplished according to very well-known methods commonly employedin organic synthetic chemistry.

Optional salification of the compounds of formula (I) or N-oxides on thepyridine ring thereof may be carried out by properly converting any ofthe free acidic or amino groups into the corresponding pharmaceuticallyacceptable salts. In this case too, the operative conditions beingemployed for the optional salification of the compounds of the inventionare all within the ordinary knowledge of the skilled person.

From all of the above, it should be clear that the above process,comprehensive of any variant thereof for the preparation of suitablecompounds of the invention, may be conveniently modified so that toadapt the reaction conditions to the specific needs, for instance bychoosing appropriate condensing agents, solvents and protective groups,as the case may be.

For example compounds of the invention of formula (I) may be preparedaccording to the route illustrated in Scheme 1.

Compounds of general formula (I) may be prepared from compounds ofgeneral formula (1a) by reaction with a compound of general formula(1b1) or (1b2) wherein R² is as defined in general formula (I), in asuitable solvent such as dimethyl sulfoxide, 1,4-dioxane,N,N-dimethylformamide or acetonitrile, in the presence of a base such asdiisopropylethylamine at a range of temperatures, preferably between RTand 100° C.

Compounds of general formula (1b1) and (1b2) are either known in theliterature or may be prepared from amines of general formula (1c)according to known literature procedures (e.g. see for referenceWO2006009741, EP1609789, which are incorporated herein by reference intheir entireties).

Compounds of general formula (1c) are either known in the literature ormay be synthesised by one skilled in the art by adapting appropriateliterature methods (e.g WO2010077836, WO2006009741, WO2008125014, J. MedChem., 2007, 50, 4016, Bulletin des Societes Chimiques Belges, 1987, 96,675-709, Organic & Biomolecular Chemistry, 2006, 4, 4158-4164, which areincorporated herein by reference in their entireties).

Compounds of general formula (1ca), i.e. compounds of formula (1c)wherein R² is a group of formula (IIIb) and R¹⁷, R¹⁸, z¹, z², z³ and z⁴are as defined above can be prepared from compounds of formula (1e),

using a suitable reducing agent such as tin (II) chloride, iron, orhydrogen gas with a suitable catalyst such as palladium on carbon, in asuitable solvent such as methanol, ethanol or acetic acid, at a range oftemperatures, preferably between RT and 100° C.

Compounds of general formula (1e) are known in the literature or may beprepared by those skilled in the art using literature methods (e.g.WO2008034008, WO20110189167, WO2010068258, which are incorporated hereinby reference in their entireties).

Alternatively, compounds of general formula (1ca) as above defined canbe prepared from compounds of formula (1f), wherein R¹⁷, R¹⁸, z¹, z², z³and z⁴ are as defined above and wherein PG is a suitable compatibleprotecting group known to those skilled in the art, such as benzyl,benzyl carbamate or tert-butyl carbamate,

using suitable deprotection conditions such as hydrochloric acid,trifluoroacetic acid, or hydrogen catalysed by for example palladium oncarbon, in a suitable solvent such as dichloromethane, methanol, ethanolor acetic acid, at a range of temperatures, preferably between 0° C. and100° C.

Compounds of general formula (1f) can be prepared by reaction ofcompounds of formula (1g), wherein R¹⁷, R¹⁸, z¹, z², z³ and z⁴ are asdefined above

with compounds of formula (1h) as above reported wherein PG is asuitable protecting group known to those skilled in the art, such asbenzyl, benzyl carbamate or tert-butyl carbamate, using suitableconditions such as in the presence of a base such as potassium carbonateor diisopropylethyl amine or under Buchwald conditions (with a catalystsuch as Pd(OAc)₂, a ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and base such as sodiumtert-butoxide), in a suitable solvent such as toluene ortetrahydrofuran, at a range of temperatures, preferably between RT and150° C.

Compounds of general formula (1g) and (1h) are known in the literatureor may be prepared by those skilled in the art by adapting appropriateliterature methods (e.g. WO2011042389, Chemistry-A European Journal,2011, 17, 6606-6609, S6606/1-S6606/38, which are incorporated herein byreference in their entireties).

Compounds of general formula (1a) may be prepared according to the routeillustrated in Scheme 2.

Compounds of general formula (1a) may be prepared from compounds ofgeneral formula (2a) by reaction with a compound of general formula(2b), (2c) or (2d), wherein G is a suitable chemical group known tothose skilled in the art selected such that it can facilitate a suitablecoupling reaction such as nucleophilic displacement or metal catalysedcross coupling. For example in cases such that when Y is —O—, —S— or—NR⁷—, examples of G may include halogen or a suitable leaving groupsuch as mesylate or triflate either directly linked or attached via agroup —(CR³R⁴)_(n)—. Examples of the coupling conditions used mayinclude using a base such as sodium hydride or potassium tert-butoxideand 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in a suitablesolvent such as N,N-dimethylformamide, toluene, 1,4-dioxane oracetonitrile at a range of temperatures, preferably between RT and 150°C. For example in cases such that when Y is —O— and G is —OH or —SH amethod to perform this coupling may involve Mitsunobu conditions(diethylazodicarboxylate/triphenylphosphine) in a suitable solvent suchas tetrahydrofuran or 1,4-dioxane at a range of temperatures preferablybetween −10° C. and 100° C. For example in cases such as when Y is —O—,—S— or —NR⁷— and G is a-group such as halogen, triflate or boronicacid/ester a method to perform this coupling may be under metal (forexample palladium or copper) catalysed coupling conditions in thepresence of a suitable ligand such as Xantphos or 1,10-phenanthroline inthe presence of a base such as caesium carbonate in a suitable solventsuch as tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide at a rangeof temperatures preferably between −10° C. and 150° C. For example incases such as when Y is —O— and G is a group such as —COOMe, —COOH,isocyanate, —OCOCl or —NHCOOCH₂CCl₃ examples of conditions to performthis coupling may involve the use of a base such as sodium hydride ortriethylamine or a coupling reagent such as HATU in a suitable solventsuch as dichloromethane, tetrahydrofuran, 1,4-dioxane orN,N-dimethylformamide at a range of temperatures preferably between −10°C. and 150° C.

Compounds of formula (2b) are commercial available, are known in theliterature or may be synthesised from compounds of formula (2e), whereinR⁸ and R⁹ are as defined for compounds of formula (I), by adaptingappropriate literature methods (e.g. WO 2006/133006, which isincorporated herein by reference in its entirety) or using methods knownto those skilled in the art such as by reacting (2e) with a suitablealkylating agent such as dibromoethane or bromoethanol in the presenceof a suitable base such as sodium hydride or potassium carbonate in asuitable solvent such as tetrahydrofuran, 1,4-dioxane orN,N-dimethylformamide at a range of temperatures preferably between −10°C. and 150° C., or by reacting (2e) with a suitable aldehyde in thepresence of a reducing agent such as sodium triacetoxyborohydride in asuitable solvent such as dichloroethane or tetrahydrofuran at a range oftemperatures preferably between −10° C. and 100° C.

Compounds of formula (2e) are commercially available, are known in theliterature or may be synthesised by those skilled in the art usingliterature methods.

Compounds of formula (2c) may be synthesised from compounds of formula(2f):

wherein X₁ and R¹² are defined as for compounds of formula (I), G is agroup such as halogen, —O-PG or —S-PG wherein PG represents a protectinggroup such as triisopropylsilyl or tert-butyldimethylsilyl (methods forwhose introduction and removal are well known by those skilled in theart) and J may represent groups such as halogen, —NH₂, —OH, —SH, —COOH,—SO₂Cl which can be modified using literature methods to introduce anappropriate group R¹⁰ by those skilled in the art. For example in casessuch as when J is halogen, a method such as nucleophilic substitutionwith a suitable alcohol, amine or thiol may be used in the presence of asuitable base such as sodium hydride, triethylamine or potassiumcarbonate in a suitable solvent such as tetrahydrofuran, 1,4-dioxane orN,N-dimethylformamide at a range of temperatures preferably between −10°C. and 150° C. For example in cases such as when J is —NH₂, —OH or —SH,a method such as alkylation may be used with a suitable alkylating agentsuch as an alkyl halide in the presence of a suitable base such assodium hydride or potassium carbonate in a suitable solvent such astetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide at a range oftemperatures preferably between −10° C. and 150° C. For example in casessuch as where J is —COOH or —SO₂Cl a method such as reaction with asuitable amine in the presence of a suitable base such as triethylamineor a coupling reagent such as HATU in a suitable solvent such astetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide at a range oftemperatures preferably between −10° C. and 150° C.

Compounds of formula (2da), i.e. compounds of formula (2a) wherein X⁴═Cmay be prepared according to the routes described in Scheme 3 herebelow:

Compounds of general formula (2da) as above defined may be prepared fromcompounds of general formula (3e) using a suitable oxidant such aschloramine T, lead tetracetate or phenyl iodine(III) diacetate, in asuitable solvent such as dichloromethane or ethanol at a range oftemperatures, preferably between RT and 100° C.

Compounds of general formula (3e) may be prepared from compounds ofgeneral formula (3a) by reaction with an aldehyde of general formula(3c) above reported. in a suitable solvent such as ethanol ortetrahydrofuran at a range of temperatures, preferably between RT and80° C.

Compounds of formula (3c) are commercially available, known in theliterature or may be prepared using literature methods by those skilledin the art.

Alternatively, compounds of formula (2da) may be prepared from compoundsof formula (3d) using a suitable dehydrating agent such as Burgess'reagent, triphenyl phosphine and hexachloroethane, phosphorusoxychloride, acetic acid or Mitsunobu conditions(diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in theabsence or presence of a suitable solvent such as tetrahydrofuran,toluene or NMP, at a range of temperatures, preferably between RT and150° C.

Compounds of formula (3d) may be prepared from compounds of formula (3a)by reaction with a compound of general formula (3b1) using a suitableacylating/dehydrating agent such astriphenylphosphine/trichloroacetonitrile in the presence of a base suchas diisopropylethylamine, in a suitable solvent such as dichloromethaneor acetonitrile, at a range of temperatures, preferably between RT and150° C.

Or by reaction with a compound of general formula (3b2) in the presenceof a base such as diisopropylethylamine, in a suitable solvent such asdichloromethane or THF at a range of temperatures preferably between−10° C. and the boiling point of the solvent.

Compounds of formulae (3b1) and (3b2) are commercially available, knownin the literature or may be prepared by literature methods by thoseskilled in the art.

Alternatively, compounds of formula (2da) as above defined may beprepared according to the route in Scheme 4:

Compounds of general formula (2da) may be prepared from compounds ofgeneral formula (4c), wherein G² may represent groups such as halogen,—CHO, —COOH, —COOEt and SO₂Cl.

For example, compounds of general formula (2da) may be prepared fromcompounds of general formula (4c), wherein G² represents halogen, usingmethods such as a metal (for example palladium) catalysed coupling witha suitable R¹¹G⁵ derivative wherein G⁵ is a group such as boronateacid/ester or stannane in a suitable solvent such as tetrahydrofuran or1,4-dioxane at a range of temperatures preferably between RT and 150° C.An alternative method may involve displacement of said halogen with asuitable group R¹¹H (such as that containing an —NH, —OH or —SH group)in the presence of a base such as sodium hydride, potassiumtert-butoxide or N,N-diethylisopropylamine in a suitable solvent such asN,N-Dimethylformamide, toluene, 1,4-dioxane or acetonitrile at a rangeof temperatures, preferably between RT and 150° C.

The group G² may be also transformed from groups such as halogen togroups such as —CHO, —COOH, —COOEt and SO₂Cl by means of metal insertionmethods known to those skilled in the art such as palladium catalysis,Grignard formation or lithium halogen exchange.

Compounds of general formula (2da) wherein R¹¹ is a group such as—CH₂—NR^(A)R^(B), —C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-OR^(D),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D), —C(O)N(R^(A)R^(B)),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-OR^(D) or—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D) may be prepared fromcompounds of general formula (4c), wherein G² represents —CHO, —COOH,—COOEt and —SO₂Cl, by reaction with a suitable amine such asHNR^(A)R^(B) etc using methods such as reductive amination (using areagent such as sodium triacetoxyborohydride) or amide/sulphonamideformation in the presence of suitable reagents such as HATU with a basesuch as N,N-diethylisopropylamine or trimethylaluminium in a suitablesolvent such as dichloromethane, N,N-dimethylformamide, toluene,1,4-dioxane or acetonitrile at a range of temperatures, preferablybetween RT and 150° C.

Compounds of general formula (4c) wherein G² is a group such as —COOEt,may be synthesised from compounds of general formula (4a) by reactionwith a compound such as diethyloxalate in the presence of an acid suchas acetic acid at a range of temperatures, preferably between RT and120° C.

Compounds of general formula (4c) wherein G² is a group such as bromineor chlorine, may be synthesised from compounds of general formula (4b)by reaction with a compound such as N-chlorosuccinimide orN-bromosuccinimide in a solvent such as chloroform at a range oftemperatures, preferably between −10° C. and RT.

Compounds of general formula (4b) may be synthesised from compounds ofgeneral formula (4a) by reaction with a compound such asdiethoxymethylacetate at a range of temperatures, preferably between RTand 100° C.

Compounds of general formula (2db), i.e. compounds of formula (2d)wherein X₄ is nitrogen, may be prepared from compounds of generalformula (4b) wherein X⁴═NH, by reaction with a suitable alkylating agentR¹¹ in the presence of a base such as caesium carbonate in a suitablesolvent such as N,N-dimethylformamide at a range of temperatures,preferably between RT and 150° C.

Alternatively, compounds of general formula (1aa), i.e. compounds offormula (1a) wherein X⁴ is CH may be prepared according to the routeillustrated in Scheme 5.

Compounds of general formula (1aa) may be prepared from compounds ofgeneral formula (5e) wherein PG is a suitable protecting group known inthe art such as Boc by using the appropriate deprotection conditionssuch as trifluoroacetic acid in a solvent such as dichloromethane at arange of temperatures, preferably between −10° C. and RT.

Compounds of general formula (5e) may be prepared from compounds ofgeneral formula (5d) using a suitable dehydrating agent such as Burgess'reagent, triphenyl phosphine and hexachloroethane, phosphorusoxychloride, acetic acid or Mitsunobu conditions(diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in theabsence or presence of a suitable solvent such as tetrahydrofuran,toluene or NMP, at a range of temperatures, preferably between RT and120° C.

Compounds of general formula (5d) may be prepared from compounds ofgeneral formula (5c) by reaction with a compound of general formula(3b1) as above defined using a suitable acylating/dehydrating agent suchas triphenylphosphine/trichloroacetonitrile in the presence of a basesuch as diisopropylethylamine, in a suitable solvent such asdichloromethane or acetonitrile, at a range of temperatures, preferablybetween RT and 150° C., or by reaction with a compound of generalformula (3b2) as above defined in the presence of a base such asdiisopropylethylamine, in a suitable solvent such as dichloromethane orTHF at a range of temperatures preferably between −10° C. and theboiling point of the solvent.

Compounds of general formula (5c) may be prepared from compounds ofgeneral formula (5b) wherein G³ is a suitable leaving group such ashalogen, by reaction with a reagent such as hydrazine monohydrate in asuitable solvent such as ethanol at a range of temperatures preferablybetween RT and 100° C.

Compounds of general formula (5b) may be prepared from compounds ofgeneral formula (5a) by reaction with a suitable protecting groupreagent known in the art such as Boc anhydride in the presence of a basesuch as triethylamine in a suitable solvent such as dichloromethane ortetrahydrofuran at a range of temperatures preferably between RT and100° C.

Compounds of general formula (5a) can be synthesized by the methodsdescribed above for the synthesis of (1a).

Compounds of general formula (2aa), i.e. compounds of formula (2a)wherein Y═O, W═NH and PG is a suitable protective group such astrifluoroacetate may be prepared according to the route illustrated inscheme 6:

Compounds of general formula (2aa) may be prepared from compounds ofgeneral formula (6b) and (6c) by removal of the protecting group PGusing methods known in the art such as aqueous sodium hydroxide in asolvent such as methanol at a range of temperatures preferably betweenRT and 100° C.

Compounds of general formula (6b), wherein PG is a protecting group,preferably trifluoroacetamide, and the group —OH is placed on thecycloalkylene portion of ring A may be prepared from compounds ofgeneral formula (6a) by using a chiral reductive method such as usingformic acid and RuCl[S,S-Tsdpen(p-cymene)] in the presence of a basesuch as triethylamine in a solvent such as N,N-dimethylformamide at arange of temperatures preferably between RT and 150° C. It will berecognised that compounds of formula (6a) may be homochiral asillustrated or be the opposite enantiomer or racemic. It will berealised by those skilled in the art that any combination ofstereocentres in (2aa) can be prepared using both enantiomers of (6a)and using RuCl[R,R-Tsdpen(p-cymene)] or RuCl[S,S-Tsdpen(p-cymene)].Compound (2a) is drawn with no defined stereocentres but any combinationcan be obtained as illustrated in Scheme 2.

Compounds of formula (6a) can be prepared from compounds of formula (6d)

using a suitable oxidant such as potassium permanganate and magnesiumsulfate in a suitable solvent methanol/water at a range of temperaturespreferably between RT and the boiling point of the solvent. It will berecognised that compounds of formula (6d) may be homochiral asillustrated or be the opposite enantiomer or racemic.

Compounds of formula (6d) can be prepared from compounds of formula (6e)where PG is a suitable protecting group such as trifluoroacetate ortert-butyl carbonate:

using ethyl trifluoroacetate or di-tert-butyl dicarbonate in thepresence of base such as triethylamine or diisopropylethylamine in asolvent such as methanol or dichloromethane at a range of temperaturespreferably between 0° C. and the boiling point of the solvent. It willbe recognised that compounds of formula (6e) may be homochiral asillustrated or be the opposite enantiomer or racemic.

Compounds of formula (6e) are known in the literature and may beprepared by those skilled in the art by adapting literature methods(e.g. for S-(+)-1-amino-1,2,3,4-tetrahydronaphthalene, see Journal ofthe Chemical Society, Perkin Transactions 1: 1985, 2039-44; for(S)-(+)-8-amino-5,6,7,8-tetrahydroquinoline, see Journal of OrganicChemistry, 2007, 72, 669-671; and for 1-aminoindan see TetrahedronLetters, 2011, 52, 1310-1312), which are incorporated herein byreference in their entireties.

Compounds of general formula (2ab), i.e. compounds of formula (2a)wherein Y═NR⁷ and W═NH, may be prepared according to the routeillustrated in scheme 7:

Compounds of general formula (2ab) may be prepared from compounds ofgeneral formula (7a) by removal of the protecting group PG using methodsknown in the art such as aqueous sodium hydroxide in a solvent such asmethanol or trifluoroacetic acid in dichloromethane at a range oftemperatures preferably between RT and 100° C.

Compounds of formula (7a) may be prepared from compounds of generalformula (6a) and amines (7b) by reaction under reductive aminationconditions, using a reducing agent such as sodium triacetoxyborohydrideand a solvent such as 1,2-dichloroethane at a range of temperaturespreferably between RT and 100° C.

Compounds for formula (7b) are known and may be prepared using knownprocedures. Compounds of formula (6a) can be prepared as describedabove.

Alternatively, compounds of formula (7a) may be prepared from compoundsof general formula (7c) wherein G⁴ is a suitable chemical group known tothose skilled in the art selected such that it can facilitate a reactionsuch as a nucleophilic substitution. For example G is a suitable leavinggroup such as halogen or mesylate which can react with a suitable amine(7b) in the presence of a suitable base such as sodium hydride orpotassium tert-butoxide and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in a suitable solventsuch as N,N-dimethylformamide, toluene, 1,4-dioxane or acetonitrile at arange of temperatures, preferably between RT and 150° C.

Compounds of formula (7c) can be prepared from compounds of formulae(6b) or (6c) using halogenating conditions such as carbon tetrabromideand triphenylphosphine in dichloromethane or activation conditions suchas methane sulfonyl chloride in dichloromethane in the presence of basesuch as diisopropylamine.

Alternatively, compounds of general formula (Id), i.e. compounds offormula (I) wherein Y═S and W═NH may be prepared according to the routeillustrated in scheme 8:

Compounds of general formula (1d) may be prepared from compounds ofgeneral formula (1ab), i.e. compounds of formula (1a) wherein Y═S andW═NH: using compounds of formula (1b1) or (1b2) in a suitable solventsuch as dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide oracetonitrile, in the presence of a base such as diisopropylethylamine ata range of temperatures, preferably between RT and 100° C.

Compounds of formula (1ab) as above defined may be prepared fromcompounds of formula (8g) using deprotection conditions such ashydrazine in methanol at a range of temperatures preferably between RTand the boiling point of the solvent.

Compounds of formula (8g) wherein Y═S, can be prepared from compounds offormula (8f) by reaction with compounds of formulae (2b), (2c) or (2d).Examples of the coupling conditions used may include using a base suchas sodium hydride or potassium tert-butoxide and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in a suitable solventsuch as N,N-dimethylformamide, toluene, 1,4-dioxane or acetonitrile at arange of temperatures, preferably between RT and 150° C. Alternativemethods to perform this coupling may involve Mitsunobu conditions(diethylazodicarboxylate/triphenylphosphine) or metal (for examplepalladium) catalysed coupling conditions in a suitable solvent such astetrahydrofuran or 1,4-dioxane at a range of temperatures preferablybetween −10° C. and 150° C. and starting from the appropriate derivativeof formula (2b), (2c), or (2d).

Compounds of formula (8f) can be prepared from compounds of formula (8e)using dithiothreitol, monopotassium phosphate, potassium carbonate in asolvent such as methanol in the presence of acetic acid at a range oftemperatures preferably between RT and the boiling point of the solvent.

Compounds of formula (8e) can be prepared from compounds of formula (8d)using 2-nitrobenzenesulfenyl chloride in acetic acid at a range oftemperatures preferably between RT and 100° C.

Compounds of formula (8d) can be prepared from compounds of formula (8c)using phthalimide, triphenylphosphine and diisopropyl azodicarboxylatein a solvent such as tetrahydrofuran at a range of temperaturepreferably between 0° C. and the boiling point of the solvent.

Compounds of formula (8c) can be prepared from compounds of formula (8b)using a reducing agent such as sodium borohydride in a solvent such asmethanol at a range of temperatures preferably between 0° C. and theboiling point of the solvent.

Compounds of formula (8b) can be prepared from compounds of formula (8a)using tert-butanethiol in the presence of a base such asdiisopropylethylamine in a solvent such as tetrahydrofuran at a range oftemperatures preferably between 0° C. and the boiling point of thesolvent.

Compounds of formula (8a) are known and can be prepared using knownmethods (e.g. 3-bromo-indan-1-one see WO 2010/108058, which isincorporated herein by reference in its entirety).

Alternatively, compounds of general formula (1ab), i.e. compounds offormula (1a) wherein Y═CH₂, W═NH and PG is a suitable protective groupsuch as trifluoroacetate may be prepared according to the routeillustrated in scheme 9:

Compounds of general formula (1ab) may be prepared from compounds ofgeneral formula (9b) by removal of the protecting group PG using methodsknown in the art such as aqueous sodium hydroxide in a solvent such asmethanol at a range of temperatures preferably between RT and 100° C.

Compounds of formula (9b) may be prepared from compounds of generalformula (9a) by reaction with a suitable reduction agent for examplehydrogen gas in the presence of a suitable catalyst such as palladium onactivated charcoal in a suitable solvent such as ethanol at a range oftemperatures between RT and 70° C. and pressures between atmospheric and4 Barr.

Compounds of formula (9a) may be prepared from compounds of generalformula (6a) by means of a reaction such as a Wittig (or one of theclosely related variants such as the Horner-Wadsworth-Emmons) with asuitable substrate such as R¹—CH₂—P(O)(OMe)₂ in the presence of asuitable base such as sodium hydride in a suitable solvent such astetrahydrofuran at a range of temperatures preferably between −10° C.and 100° C.

Compounds such as R¹—CH₂—P(O)(OMe)₂ may be synthesised from compounds ofthe general formula R¹—CH₂—Hal wherein Hal represents a halogen such as—Br or —Cl by reaction with a compound such as trimethylphosphite at arange of temperatures preferably between 0° C. and 100° C.

Compounds such as R¹—CH₂—Hal may be synthesised from compounds offormula R¹—CH₃ by means of a reaction such as a radical halogenationusing a reagent such as N-bromosuccinimide in the presence of a catalystsuch as AIBN in a suitable solvent such as carbon tetrachloride at arange of temperatures preferably between 0° C. and 80° C. Compounds suchas R¹—CH₂—Hal may also be synthesized from compounds formula R¹—CH₂—OHby means of using halogenating conditions such as carbon tetrabromideand triphenylphosphine in dichloromethane or activation conditions suchas methane sulfonyl chloride in dichloromethane in the presence of basesuch as diisopropylamine.

Compounds such as R¹—CH₃ and R¹—CH₂—OH may be prepared by methodsoutlined above for compounds (2b), (2c) and (2d).

Compounds of the invention of formula (1ac), i.e. compounds of formula(1a) where Y═(CR⁵R⁶)_(n) and W═NH, may be prepared according to theroute illustrated in Scheme 10.

Compounds of formula (1 ac) may be prepared from compounds of formula(10c) wherein PG is a suitable protecting group known to those skilledin the art, such as trifluoroacetamide, tert-butyl carbamate and benzylcarbamate by using suitable deprotection conditions such as, sodiumhydroxide in methanol, trifluoroacetic acid in dichloromethane orhydrogen gas catalysed by for example palladium on carbon in ethanol, ata range of temperatures, preferably between 0° C. and 100° C.

Compounds of formula (10c) may be prepared from compounds of formula(10b) wherein PG is a suitable known protecting group, such astrifluoroacetamide, tert-butyl carbamate and benzyl carbamate by usinghydrogen gas in the presence of a catalyst such as palladium on carbon,in a suitable solvent such as methanol or ethanol, in the presence orabsence of an acid such as HCl, at a range of temperatures, preferablybetween 0° C. and 100° C.

Compounds of formula (10b) may be prepared from compounds of formula(10a) and (10f) by a reaction such as a cross-coupling using a suitablecatalyst such as tetrakis(triphenylphosphine)palladium (0) or palladiumacetate, and a base such as diisopropylethylamine, sodium tert-butoxideor caesium carbonate in a suitable solvent such as NMP, toluene or DMF,at a range of temperatures, preferably between 0° C. and 100° C.Alternatively (10b) may be prepared by adapting known procedures (e.gthose reported in WO2009/022633, which is incorporated herein byreference in its entirety).

Compounds of formula (10f) are known in the literature or may beprepared by those skilled in the art by adapting literature procedures(e.g WO2008/063287, which is incorporated herein by reference in itsentirety).

Compounds of formula (10a) may be prepared from compounds of formula(6a) using a triflating agent such as triflic anhydride, in the presenceof a suitable base such as pyridine or2,6-bis(tert-butyl)-4-methylpyridine, in a solvent such asdichloromethane or chloroform at a range of temperatures, preferablybetween 0° C. and boiling point of the solvent. Alternatively (10a) maybe prepared by adapting literature procedures (e.g those described inWO2009/022633, which is incorporated herein by reference in itsentirety).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the experimental section:

AcOH=acetic acid;

CDCl₃=deuterated chloroform;

DCM=dichloromethane;

DEAD=Diethyl azodicarboxylate;

DIAD=Diisopropyl azodicarboxylate;

DIPEA=diisopropylethylamine;

DMAP=N,N-dimethylaminopyridine;

DMF=N,N-dimethylformamide;

d₄-MeOD=deuterated methanol;

d₆-DMSO=deuterated dimethyl sulfoxide;

EDC=1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide Hydrochloride;

EtOAc=ethyl acetate;

EtOH=ethanol;

Et₂O=diethyl ether;

Et₃N=triethylamine;

EtNiPr₂=diisopropylethylamine;

FCC=flash column chromatography;

H=hour;

HATU=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate;

HOBt=1-hydroxy-benzotriazole;

HPLC=high performance liquid chromatography;

IMS=Industrial Methylated Spirits;

LCMS=liquid chromatography mass spectrometry;

NaOH=sodium hydroxide;

MeCN=acetonitrile;

MeOH=Methanol;

min=minutes;

NH₃=ammonia;

NIS=N-iodosuccinimide;

NMR=nuclear magnetic resonance;

RT=room temperature;

Rt=retention time;

sat.=saturated;

SCX-2=strong cation exchange chromatography;

TBAF=tetrabutylammonium fluoride;

TFA=trifluoroacetic acid;

THF=Tetrahydrofuran;

H₂O=water;

Xantphos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;

X-Select=Waters X-select HPLC column;

IPA=propan-2-ol;

LDA=lithium diisopropylamide;

MDAP=mass-directed auto-purification;

Ph₃P=triphenylphosphine;

TBAF=tetrabutylammonium fluoride.

In the procedures that follow, after each starting material, referenceto an Intermediate/Example number is usually provided. This is providedmerely for assistance to the skilled chemist. The starting material maynot necessarily have been prepared from the batch referred to.

When reference is made to the use of a “similar” or “analogous”procedure, as will be appreciated by those skilled in the art, such aprocedure may involve minor variations, for example reactiontemperature, reagent/solvent amount, reaction time, work-up conditionsor chromatographic purification conditions.

The nomenclature of structures was assigned using Autonom 2000 Namesoftware from MDL Inc. When the nomenclature of structures could not beassigned using Autonom, ACD/Name software utility part of the ACD/LabsRelease 12.00 Product Version 12.5 (Build 45133, 16 Dec. 2010) was used.Stereochemical assignments of compounds are based on comparisons withdata reported in WO2008/043019, which is incorporated herein byreference in its entirety, for key intermediates. All reactions werecarried out under anhydrous conditions and an atmosphere of nitrogen orargon unless specified otherwise. Unless otherwise stated alltransformations were carried at RT.

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer witha 5 mm inverse detection triple resonance probe operating at 400 MHz oron a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detectiontriple resonance TXI probe operating at 400 MHz or on a Bruker AvanceDPX 300 spectrometer with a standard 5 mm dual frequency probe operatingat 300 MHz. Shifts are given in ppm relative to tetramethylsilane (δ=0ppm). J values are given in Hz through-out. NMR spectra were assignedusing DataChord Spectrum Analyst Version 4.0.b21 or SpinWorks version 3.

Where products were purified by flash column chromatography (FCC),‘flash silica’ refers to silica gel for chromatography, 0.035 to 0.070mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressureof nitrogen up to 10 p.s.i accelerated column elution or use of theCombiFlash® Companion purification system or use of the Biotage SP 1purification system. All solvents and commercial reagents were used asreceived.

Compounds purified by preparative HPLC were purified using aC18-reverse-phase column (100×22.5 mm i.d Genesis column with 7 μmparticle size), or a Phenyl-Hexyl column (250×21.2 mm i.d. Gemini columnwith 5 μm particle size), UV detection between 220-254 nm, flow 5-20mL/min), eluting with gradients from 100-0 to 0-100% water/acetonitrile(containing 0.1% TFA or 0.1% formic acid) or water/MeOH (containing 0.1%TFA or 0.1% formic acid), or a C18-reverse-phase column (19×250 mm,XBridge OBD, with 5 μm particle size), eluting with gradients from 100-0to 0-100% water/acetonitrile (containing 0.1% NH₄OH); or a ChiralPak ICcolumn (10×250 mm i.d., with 5 μm particle size), unless otherwiseindicated. Fractions containing the required product (identified by LCMSanalysis) were pooled, the organic solvent removed by evaporation, andthe remaining aqueous residue lyophilised, to give the final product.Products purified by preparative HPLC were isolated as free base,formate or TFA salts, unless otherwise stated.

The Liquid Chromatography Mass Spectroscopy (LCMS) and HPLC systems usedare:

Method 1.

Waters Platform LC Quadrupole mass spectrometer with a C18-reverse-phasecolumn (30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μL split to MS with in-line HP1100 DADdetector). MS ionization method—Electrospray (positive and negativeion).

Method 2.

Waters ZMD quadrupole mass spectrometer with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5Detection—MS, ELS, UV (200 μL split to MS with in-line Waters 996 DADdetector). MS ionization method—Electrospray (positive and negativeion).

Method 3.

Waters ZMD quadrupole mass spectrometer with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.05 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μL split to MS with in-line HP1100 DADdetector). MS ionization method—Electrospray (positive and negativeion).

Method 4.

VG Platform II quadrupole spectrometer with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 μm particle size, elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.30 2.0 95 5 4.30 2.05 95 5.30 2.0 5 95 5.80 2.0 95 5 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μl/min split to the ESI source with inlineHP1050 DAD detector). MS ionization method—Electrospray (positive andnegative ion).

Method 5.

Waters micromass ZQ2000 quadrupole mass spectrometer with an Acquity BEHC18 1.7 um 100×2.1 mm, Acquity BEH Shield RP18 1.7 um 100×2.1 mm orAcquity HSST3 1.8 um 100×2.1 mm, maintained at 40° C. Elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 0.4 95 5 0.40 0.4 95 5 6.00 0.45 95 6.80 0.4 5 95 7.00 0.4 95 5 8.00 0.4 95 5

Detection—MS, UV PDA. MS ionization method—Electrospray (positive andnegative ion).

Method 6.

Phenomenex Gemini C18-reverse-phase column (250×21.20 mm 5 μm particlesize), elution with A: water+0.1% formic acid; B: CH₃CN+0.1% formicacid. Gradient—90% A/10% B to 2% A/98% B over 20 min—flow rate 18mL/min. Detection—In-line UV detector set at 254 nM wavelength.

Method 7.

Agilent 1260 infinity purification system. Column: XSELECT CSH Prep C18OBD, particle size 5 μm, 30×150 mm, RT. Elution with A: water+0.1%formic acid; B: CH₃CN+0.1% formic acid. Gradient—90% A/10% B to 2% A/95%B over 22 min —flow rate 60 mL/min. Detection—In-line Agilent 6100series single Quadrupole LC/MS.

Method 8.

Agilent 1260 infinity purification system. Column: XBridge Prep C18 OBD,particle size 5 μm, 30×150 mm, RT. Elution with A: water+0.1% ammonia;B: CH₃CN+0.1% ammonia. Gradient—90% A/10% B to 2% A/95% B over 22min—flow rate 60 mL/min. Detection—In-line Agilent 6100 series singleQuadrupole LC/MS.

Method 9.

Waters ZQ quadrupole mass spectrometer with a C18-reverse-phase column(30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient - Time flow mL/min % A % B 0.00 2.0 95 5 0.30 2.0 95 5 4.30 2.05 95 5.30 2.0 5 95 5.8 2.0 95 5 6.00 2.0 95 5

Detection—MS, ELS, UV (200 L split to MS with in-line HP1100 DADdetector). MS ionization method—Electrospray (positive and negativeion).

Intermediate A. (1R,4S)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-ol

a. 2,2,2-Trifluoro-N—(S)-1,2,3,4-tetrahydro-naphthalen-1-yl-acetamide(Intermediate Aa)

To a mechanically stirred solution of(S)-(+)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (CAS: 23357-52-0, 175g, 1.19 mol) and triethylamine (250 mL, 1.79 mol) in MeOH (1.75 L),ethyl trifluoroacetate (170 mL, 1.43 mol) was added dropwise at a rateto maintain the internal temperature below 30° C. (ca. over 20 min). Theresulting solution was stirred at RT overnight. The mixture wasconcentrated in vacuo to give a solid. This was partitioned between DCM(1 L) and water (1 L). The layers were separated and the aqueous layerwas extracted with DCM (2×600 mL). The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo toyield Intermediate Aa (289.4 g, 100%). ¹H NMR (400 MHz, CDCl₃):1.80-1.95 (3H, m), 2.05-2.15 (1H, m), 2.75-2.90 (2H, m), 5.18-5.25 (1H,q, J=5.0 Hz), 6.38-6.48 (1H, br s), 7.12-7.16 (1H, m), 7.20-7.26 (3H,m).

b.2,2,2-Trifluoro-N—((S)-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide(Intermediate Ab)

A 20 L flask was charged with Intermediate Aa (288 g, 1.19 mol) andacetone (7 L). Magnesium sulfate monohydrate (328 g, 2.37 mol) in water(3 L) was added and the mixture stirred mechanically, and cooled tointernal temperature ˜1.5° C. Potassium permanganate (562.1 g, 3.56 mol)was then added in 7 equal portions (i.e. 80.3 g) every 15 min for 105min. Water (0.5 L) was added and the resulting mixture was stirred at RTfor 17 h. The mixture was cooled to 15° C. and a solution of sodiumthiosulfate pentahydrate (883 g, 3.56 mol) in water (3 L) was addeddropwise over 1 h, whilst maintaining internal temperature below 18° C.The resulting slurry was stirred for 1 h and the mixture left to standat RT overnight. A solid had settled at the bottom of the flask and thesolution was decanted and then concentrated to leave a residue. Theremaining solid was treated with ethyl acetate (7 L) and water (2 L) andthe mixture was filtered through Celite. The filtrate was combined withthe residue isolated above. The mixture was separated and the aqueouslayer extracted with ethyl acetate (2×1 L). The organics were combinedand drying agent (Na₂SO₄) and decolourising charcoal were added. Themixture was filtered through Celite and concentrated to dryness in vacuoto yield Intermediate Ab (260 g, 85%). ¹H NMR (400 MHz, CDCl₃):2.20-2.30 (1H, dddd, J=13.3, 10.0, 8.8, 4.5 Hz), 2.43-2.52 (1H, dddd,J=13.3, 7.2, 4.6, 4.6 Hz), 2.67-2.77 (1H, ddd, J=17.4, 10.1, 4.6 Hz),2.78-2.88 (1H, ddd, J=17.4, 7.1, 4.6 Hz), 5.39-5.47 (1H, td, J=8.5, 4.5Hz), 7.32-7.37 (1H, d, J=7.7 Hz), 7.44-7.49 (1H, t, J=7.6 Hz), 7.59-7.64(1H, td, J=7.6, 1.4 Hz), 8.03-8.07 (1H, dd, J=7.7, 1.4 Hz).

c.2,2,2-Trifluoro-N-((1S,4R)-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide(Intermediate Ac)

A solution of Intermediate Ab (161 g, 624 mmol) in DMF (2 L) was vacuumdegassed with Argon.[N-[(1R,2R)-2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-TI)-1-methyl-4-(1-methylethyl)benzene]-ruthenium(CAS: 192139-92-7, 9.95 g, 15.6 mmol) was then added. Formic acid (57.5g, 1.25 mol) was added slowly to ice cold triethylamine (126 g, 1.25mol) with stirring, this was then added to the DMF solution. Theresulting reaction mixture was heated to 50° C. (internal temperature)for 41 h with stirring. LCMS analysis of the reaction indicated it wasincomplete, therefore a solution of formic acid (14.4 g, 313 mmol) wasadded slowly to ice cold triethylamine (31.6 g, 312 mmol), this was thenadded to the reaction mixture. Heating was continued for an additional22 h. After cooling, the mixture was concentrated in vacuo to give anorange residue. The residue was diluted with ethyl acetate (1.5 L) andthe solution washed with brine (2×0.5 L). The organics were dried(Na₂SO₄), filtered and concentrated in vacuo. Purification by columnchromatography (Silica, 3 Kg, 0-50% ethyl acetate in cyclohexane) gaveIntermediate Ac (118 g, 73%). 97.5 d.e. % determination by LCMS (Method4): Rt 3.37 min, M-H=258 (93.7%, desired); Rt 3.25 min, M-H=258 (1.2%,trans isomer). ¹H NMR (400 MHz, CDCl₃): 1.88-1.92 (1H, d, J=4.8 Hz),1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H,br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).

d. (1R,4S)-4-Amino-1,2,3,4-tetrahydro-naphthalen-1-ol (Intermediate A)

To a stirred solution of Intermediate Ac (117 g, 451 mmol) in methanol(0.7 L), 6N sodium hydroxide solution (190 mL, 1.14 mol) was added andstirred at RT for 20 h. The mixture was concentrated in vacuo and theresidue was diluted with ethyl acetate (1 L) and water (0.5 L).Concentrated HCl solution (95 mL, 1.14 mol) was added slowly withstirring. Additional HCl was used to adjust the pH of the aqueous layerto pH=2. The mixture was then separated and the organic layer wasextracted with HCl solution (2M aqueous, 3×500 mL). The combined aqueouslayers were basified to pH ˜12, by addition of concentrated NH₄OHsolution, and then extracted in to ethyl acetate (5×750 mL). Thecombined organic extracts were washed with brine (200 mL), dried(Na₂SO₄), filtered and concentrated in vacuo (50.8 g). This material wasrecrystallized (cyclohexane/ethyl acetate [2:1], 350 mL) to provideIntermediate A (44.4 g, 60%). ¹H NMR (400 MHz, d₆-DMSO): 1.66-1.90 (4H,m), 3.71-3.77 (1H, t, J⁼5.4 Hz), 4.46-4.54 (1H, t, J=5.4 Hz), 7.14-7.22(2H, m), 7.32-7.38 (1H, m), 7.40-7.46 (1H, m).

Intermediate B.(1S,4R)-4-[3-((S)-2-Methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

a. (R)-Hydroxy-phenyl-acetate(S)-2-methyl-piperidinium (Intermediate Ba)

2-Methylpiperidine (CAS: 109-05-7; 99.7 g, 1.00 mol) was dissolved inMeOH (100 mL) in a 2 L Florentine flask and cooled in an ice bath.(R)-(−)-Mandelic acid (CAS: 611-71-2; 152.9 g, 1.00 mol) was then addedand the reagents stirred with gentle heating until a homogenous solutionresulted. The solution was left to cool, and Et₂O (900 mL) was added.The flask walls were scratched to aid crystallisation, and then storedin a fridge for 18 h. The resulting crystals were then filtered off, andwashed with cold Et₂O. The product was recrystallized again from MeOH(100 mL) and Et₂O (500 mL) and left in a fridge for 48 h. The crystalswere filtered off, washed with Et₂O and dried in a vacuum oven at 50° C.overnight to afford Intermediate Ba (67.0 g, 53%) as colorless crystals.¹H NMR (300 MHz, d₆-DMSO): 1.12 (3H, d, J=6.5 Hz), 1.20-1.57 (3H, m),1.58-1.74 (3H, m), 2.72 (1H, dt, J=3.2, 12.4 Hz), 2.88-3.02 (1H, m),3.06-3.18 (1H, m), 4.51 (1H, s), 7.11-7.19 (1H, m), 7.19-7.29 (2H, m),7.33-7.42 (2H, m).

Diastereomeric purity was determined using Marfey's method; IntermediateBa (1 mg, 3.68 μmol) was dissolved in EtOAc (1 mL) and H₂O (1 mL) andMarfeys reagent was added(N_(α)-(2,4-Dinitro-5-fluorophenyl)-L-alaninamide, FDAA [CAS95713-52-3], 1 mg, 3.68 μmol) followed by saturated NaHCO₃ solution (50μL) and heated to 50° C. for 1 h. The mixture was then diluted with H₂O(1 mL) and subjected to analytical HPLC (Waters X-Select C18, 2.5 μm,4.6×50 mm, 32-34% CH₃CN/H₂O (+0.1% formic acid), 16 min gradient, 1mL/min, 340 nm). Rt 10.82 min, >99% d.e.

Racemic 2-methylpiperidine was also subjected to Marfey's method; HPLC:Rt 10.75 min (50%), 11.58 min (50%).

b. (S)-2-Methyl-piperidine-1-carbonyl chloride (Intermediate Bb)

Intermediate Ba (12.0 g, 47.8 mmol) was treated with aqueous NaOHsolution (1N; 96 mL, 96.0 mmol) and extracted into DCM (2×75 mL). Thissolution containing (S)-2-methyl piperidine was transferred to a3-necked RB flask, stirred under an inert atmosphere and cooled in anice-bath before pyridine (11.6 mL, 144 mmol) was added followed bytriphosgene (14.2 g, 47.8 mmol) during 30 min at <10° C. The coolingbath was removed after 30 min and the mixture stirred at RT for afurther 3.5 h. Reaction was quenched by very careful addition of aqueousHCl (1N, 300 mL) at 0-5° C. After 30 min the phases were separated andthe aqueous layer extracted with DCM (2×100 mL). Combined DCM extractswere washed with brine, dried (MgSO₄), passed through a phase separationcartridge and concentrated in vacuo to give Intermediate Bb (8.6g, >100%). ¹H NMR (300 MHz, CDCl₃): 1.25 (3H, d, J=6.8 Hz), 1.40-1.80(6H, m), 3.0 (1H, br), 4.12-4.21 (1H, m), 4.56-4.67 (1H, m).

c. (S)-2-Methyl-piperidine-1-carboxylic acidN′-(5-fluoro-pyridin-2-yl)-hydrazide (Intermediate Bc)

A stirred solution of Intermediate Bb (17.2 g, assumed to be 95.5 mmol)and (5-fluoro-pyridin-2-yl)-hydrazine (12.1 g, 95.5 mmol) in DCM (300mL) at RT was treated with DIPEA (34.0 mL, 195 mmol) during 5 min. Thismixture was continued to be stirred at RT for 4 days before being addedto water (500 mL) and phases separated. The aqueous layer was furtherextracted into DCM (4×100 mL), combined extracts washed with brine,dried (MgSO₄), passed through a phase separation cartridge andconcentrated in vacuo to give a solid.

This product was treated with Et₂O—pentane and the resultant solidsfiltered off and dried to give Intermediate Bc (18.7 g, 77%). LCMS: Rt2.26 min, m/z 253 [MH⁺]. ¹H NMR (300 MHz, CDCl₃): 1.23 (3H, d, J=6.9Hz), 1.40-1.74 (6H, m), 2.97 (1H, td, J=13.1, 3.0 Hz), 3.82-3.91 (1H,m), 4.27-4.38 (1H, m), 6.54 (1H, s), 6.78 (1H, ddd, J=9.1, 3.7, 0.6 Hz),7.30 (1H, ddd, J=9.1, 7.8, 2.9 Hz), 8.00 (1H, d, J=2.6 Hz).

d.6-Fluoro-3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(Intermediate Bd)

To a stirred solution of Intermediate Bc (14.7 g, 58.3 mmol), Ph₃P (30.6g, 116.5 mmol) and Et₃N (33.0 mL, 236.8 mmol) in THF (300 mL) at RT wasadded hexachloroethane (27.6 g, 116.6 mmol) during 10 min before thenheating at 60° C. overnight. The cooled mixture was filtered andconcentrated in vacuo to give a residual oil which was dissolved in DCM(200 mL) and extracted into dilute HCl (2M) until most product had beenremoved from the DCM phase by LCMS. These aqueous extracts were treatedwith solid NaOH (with cooling) to achieve ˜pH9 and extracted into DCM.Combined DCM extracts were washed with brine, dried (MgSO₄), passedthrough a phase separation cartridge and concentrated in vacuo to giveIntermediate Bd (11.3 g, 82%). LCMS: Rt 2.99 min, m/z 235 [MH⁺]. ¹H NMR(300 MHz, d₆-DMSO): 0.89 (3H, d, J=6.3 Hz), 1.40-1.88 (6H, m), 2.85-2.96(1H, m), 3.18 (1H, dt, J=12.0, 4.5 Hz), 3.28-3.35 (1H, m), 7.42 (1H,ddd, J=10.0, 8.0, 2.3 Hz), 7.76 (1H, ddd, J=10.0, 4.9, 0.9 Hz),8.31-8.35 (1H, m).

e.(1S,4R)-4-[3-((S)-2-Methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate B)

Sodium hydride (60% dispersion in oil, 12.0 g, 300 mmol) was suspendedin DMF (800 mL) and cooled to 0° C. using an ice bath. Intermediate A(24.5 g, 150 mmol) was then added in small portions under N₂ and theresulting suspension was stirred at RT for 45 min (CARE: gas evolution).A solution of Intermediate Bd (35.1 g, 150 mmol) in dry DMF (200 mL) wasadded and the solution stirred at RT for 18 h. The solution wasconcentrated in vacuo, the residue was poured into a mixture of brine/1Naqueous NaOH/H₂O (1:1:1; 200 mL); the product was extracted usingmixture of EtOAc and Me-THF (300 mL×5). The organic extracts werecombined, washed with a small amount of brine, dried over MgSO₄ andconcentrated under reduced pressure. The product was purified by FCC,eluting with 0-20% [2M NH₃ in MeOH] in DCM, to provide the titlecompound (27.1 g, 48%). LCMS (Method 3): Rt 2.29 min, m/z 378 [MH⁺].

Intermediate C.(1S,4R)-4-[3-((2S,6R)-2,6-Dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

a. (2S,6R)-2,6-Dimethyl-piperidine-1-carbonyl chloride (Intermediate Ca)

To a solution of triphosgene (20.8 g, 70.0 mmol) in DCM (400 mL) at 5°C. was added pyridine (16.2 mL, 200 mmol) dropwise over 10 min,maintaining the temperature below 10° C. The solution was stirredbetween 5-10° C. for 1 h, then cis-2,6-dimethyl piperidine (CAS:766-17-6; 27.0 mL, 200 mmol) was added dropwise over 10 min and theresulting red solution stirred at RT for 4 days. The solution was cooledto 3° C., then a pre-cooled (3° C.) aq. HCl solution (1M, 400 mL) wasadded and the mixture stirred at 5° C. for 30 min. The aqueous layer wasextracted with DCM (200 mL), then the combined organics passed through ahydrophobic frit and concentrated under vacuum affording Intermediate Caas a red oil (31.5 g, 90%). ¹H NMR (300 MHz, CDCl₃): 1.30 (6H, d, J=7.09Hz), 1.49-1.87 (6H, m), 4.46-4.56 (2H, m).

b. (2S,6R)-2,6-Dimethyl-piperidine-1-carboxylic acidN-(5-fluoro-pyridin-2-yl)-hydrazide (Intermediate Cb)

A dark red solution of (5-fluoro-pyridine-2-yl)-hydrazine (21.7 g, 171mmol), Intermediate Ca (31.5 g, 180 mmol) and DIPEA (44.7 mmol, 256mmol) in DCM (350 mL) was stirred at RT for 4 days. Water (350 mL) wasadded, then the aqueous extracted with DCM (100 mL). The combinedorganics were passed through a hydrophobic frit and concentrated undervacuum to leave a solid. Trituration with diethyl ether/pentane (1:4,150 mL), and drying under vacuum at 50° C. left Intermediate Cb (31.7 g,70%, ˜90% purity). LCMS: Rt 2.58 min, m/z 289 [MH⁺]. ¹H NMR (300 MHz,CDCl₃): 1.29 (6H, d, J=7.0 Hz), 1.45-1.89 (6H, m), 4.26 (2H, apparentquin, J=6.5 Hz), 6.53 (1H, s), 6.65 (1H, br s), 6.77 (1H, dd, J=9.0, 3.6Hz), 7.29-7.28 (1H, ddd, J=9.0, 8.0, 3.0 Hz), 8.02 (1H, d, J=2.9 Hz).

c.3-((2S,6R)-2,6-Dimethyl-piperidin-1-yl)-6-fluoro-[1,2,4]triazolo[4,3-a]pyridine(Intermediate Cc)

To a dark red suspension of Intermediate Cb (27.4 g, 103 mmol) andpyridine (25.0 mL, 309 mmol) in toluene (250 mL) at 50° C. was addedPOCl₃ (11.0 mL, 118 mmol) in 3 portions at 30 s intervals (CARE:exotherm to 70° C.). The suspension was stirred at 50° C. for 1 h, thencooled to RT. Water (100 mL) and sat. aq. NaHCO₃ solution (100 mL) wereadded (CARE: gas evolution) and the mixture stirred at RT for 30 min.The aqueous was extracted with EtOAc (2×250 mL), then the combinedorganics washed with brine (250 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo to leave a oil (26.3 g). The oil was redissolvedin MeOH (150 mL) then charcoal (6 g) was added and the mixture swirledfor 30 min. The suspension was filtered through Celite and thefiltercake washed with MeOH (25 mL). The combined organics wereconcentrated in vacuo to leave a red oil. The residue was azeotropedwith pentane (25 mL) affording a solid (24.0 g). The solid was slurriedin diethyl ether-pentane (1:1, 40 mL), filtered and dried in vacuo toleave Intermediate Cc (20.65 g, 81%). The mother liquor was concentratedin vacuo, the residue dissolved in hot cyclohexane (50° C., 30 mL), thencooled to RT and allowed to stand for over the weekend. The mixture wasfiltered, the solid washed with cyclohexane (5 mL) then dried in vacuoat 45° C. to leave additional Intermediate Cc (1.8 g, 6%). LCMS: Rt 3.30min, m/z 249 [MH⁺]. ¹H NMR (300 MHz, CDCl₃): 0.68 (6H, d, J=6.2 Hz),1.36-1.49 (2H, m), 1.52-1.68 (1H, m), 1.75-1.90 (3H, m), 3.29-3.40 (2H,m), 7.16 (1H, ddd, J=10.0, 7.6, 2.3 Hz), 7.67 (1H, dd, J=10.0, 4.7 Hz),8.03 (1H, t, J=2.7 Hz).

d.(1S,4R)-4-[3-((2S,6R)-2,6-Dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate C)

To a solution of Intermediate A (6.59 g, 40.4 mmol) in dry DMF (80 mL)under N₂ was added sodium hydride (60% dispersion in oil, 3.20 g, 80.0mmol) and the resulting solution was stirred at RT for 45 min (CARE: gasevolution). A solution of Intermediate Cc (9.93 g, 40.0 mmol) in dry DMF(20 mL) was added and the solution stirred at RT under N₂ for 24 h. Thereaction was quenched carefully with saturated aqueous NH₄Cl solution(CARE: gas evolution) and H₂O. The mixture was stirred for 30 min.Concentration in vacuo gave a gum, which was dissolved in MeOH (125 mL),charcoal was added to the solution and the mixture was stirred at RT for1 h. The mixture was filtered through Celite and the solution wasevaporated under reduced pressure to afford a residue. The residue wassuspended in H₂O (100 mL), extracted with EtOAc 3×100 mL); the combinedorganics was washed with brine (75 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to leave a foam (14.6 g). The foam was trituratedwith pentane (2×75 mL) using sonication and stirring, the solution wasdecanted and the solid was left to dry under vacuum and at RT affordingIntermediate C (14.21 g, 90%). LCMS (Method 3): Rt 2.32 min, m/z 392[MH⁺].

Intermediate D.(1S,4R)-4-(3-Piperidin1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-cis-1,2,3,4-tetrahydro-naphthalen-1-ylamine

a. Piperidine-1-carboxylic acid N′-(5-fluoro-pyridin-2-yl)-hydrazide(Intermediate Da)

1-Piperidine carbonyl chloride (348 mg, 0.30 mL, 2.36 mmol) was addeddropwise to a solution of 5-fluoro-2-hydrazinyl-pyridine (see forreference WO2010/022076, which is incorporated herein by reference; 0.30g, 2.36 mmol) and DIPEA (1.20 mL, 7.08 mmol) in DCM (10 mL) at RT undernitrogen and the mixture stirred for 2 h. The solution was washed withwater (2×15 mL) and dried (Na₂SO₄). The solvent was evaporated and theresidue triturated (diethyl ether) to afford Intermediate Da (475 mg,84%). LCMS (Method 1): Rt 1.82 min, m/z 239 [MH⁺].

b. 6-Fluoro-3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridine(Intermediate Db)

Hexachloroethane (826 mg, 3.92 mmol) was added portionwise to a solutionof Intermediate Da (466 mg, 1.95 mmol), triphenylphosphine (1.03 g, 3.92mmol) and triethylamine (1.10 mL, 7.83 mmol) in dry THF (30 mL) at RT,and the mixture stirred for 2 h. The resulting precipitate was filteredoff and the filtrate evaporated. The residue was purified by SCX-2,eluting with MeOH followed by 2M NH₃ in MeOH, to give Intermediate Db asa pale orange coloured gum (206 mg, 48%). LCMS (Method 1): Rt 2.44 min,m/z 221 [MH⁺].

c.(1S,4R)-4-(3-Piperidin1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-cis-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate D)

Intermediate A (100 mg, 0.61 mmol) was added portionwise to a suspensionof sodium hydride (60% in mineral oil, 73.0 mg, 1.84 mmol) in dry DMF (2mL) at RT, and the mixture stirred for 15 min. Intermediate Db (135 mg,0.61 mmol) was then added in one portion and the mixture heated at 60°C. for 1 h. After cooling, saturated NH₄Cl (ca. 0.2 mL) was added. Themixture was then partitioned between water (15 mL) and ethyl acetate(3×15 mL) and the combined organic extracts washed with brine (2×15 mL)and dried (Na₂SO₄). The solvent was evaporated and the residue purifiedby SCX-2, eluting with MeOH followed by NH₃ in MeOH, to giveIntermediate D (133 mg, 60%). LCMS (Method 1): Rt 1.95 min, m/z 364[MH⁺].

Intermediate E.(1S,4R)-4-[3-((S)-1-Methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

a. (S)-1-Methyl-pyrrolidine-2-carboxylic acid[N′-(5-fluoro-pyridin-2-yl)-hydrazide (Intermediate Ea)

EDC (271 mg, 1.41 mmol) was added portionwise to a solution of5-fluoro-2-hydrazinyl-pyridine (for reference procedure seeWO2010/02207, which is incorporated herein by reference 6; 0.15 g, 1.18mmol), N-methyl-L-proline monohydrate (0.20 g, 1.36 mmol) and HOBt (16mg, 0.12 mmol) in dry DCM (5 mL) at RT and stirred for 16 h. Thesolution was diluted with DCM (15 mL), washed with water (150 mL), dried(Na₂SO₄) and evaporated to give Intermediate Ea (189 mg, 67%). LCMS(Method 1): Rt 0.31 min, m/z 239 [MH⁺].

b.6-Fluoro-3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine(Intermediate Eb)

Hexachloroethane (375 mg, 1.59 mmol) was added portionwise to a solutionof Intermediate Ea (189 mg, 0.79 mmol), triphenylphosphine (416 mg, 1.59mmol) and triethylamine (0.44 mL, 3.17 mmol) in dry THF (10 mL) at RTand stirred for 4 h. The resulting precipitate was filtered off and thefiltrate evaporated. The residue was purified by SCX-2, eluting withMeOH followed by 2M NH₃ in MeOH gave Intermediate Eb (136 mg, 78%). LCMS(Method 1): Rt 0.45 min, m/z 221 [MH⁺].

c.(1S,4R)-4-[3-((S)-1-Methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine.(Intermediate E)

Intermediate A (128 mg, 0.77 mmol) was added portionwise to a suspensionof sodium hydride (60% in mineral oil, 92 mg, 2.30 mmol) in dry DMF (3mL) at RT and stirred for 15 min. Intermediate Eb (169 mg, 0.77 mmol)was then added in one portion and the mixture heated at 60° C. for 4 h.After cooling, saturated aqueous NH₄Cl (ca. 0.2 mL) was added. Themixture was partitioned between water (10 mL) and ethyl acetate (3×10mL). The aqueous phase was concentrated in vacuo and the residuepurified by SCX-2, eluting with MeOH followed by 2M NH₃ in MeOH, to giveIntermediate E (103 mg, 36%). LCMS (Method 1): Rt 1.34 min, m/z 364[MH⁺].

Intermediate F.(1S,4R)-4-(3-[1,4]Oxazepan-4-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamine

a. 6-Fluoro-[1,2,4]triazolo[4,3-a]pyridine (Intermediate Fa)

(5-Fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) in diethoxymethylacetate (5 mL) was stirred at RT for 2 h. The resulting precipitate wasdiluted with cyclohexane (5 mL) and filtered to give Intermediate Fa(379 mg, 70%). ¹H NMR (400 MHz, CDCl₃): 7.25 (1H, m), 7.84 (1H, m), 8.09(1H, t, J=2.5 Hz), 8.84 (1H, s).

b. 3-Chloro-6-fluoro-[1,2,4]triazolo[4,3-a]pyridine (Intermediate Fb)

A solution of Intermediate Fa (789 mg, 5.98 mmol) andN-chlorosuccinimide (878 mg, 6.57 mmol) in chloroform (15 mL) was heatedat 65° C. overnight. The cooled mixture was washed with sat. aqueousNaHCO₃ solution (2×15 mL) and dried (Na₂SO₄). The solvent wasevaporated, then the residue suspended in diethyl ether (10 mL) andfiltered to give Intermediate Fb (730 mg, 76%). LCMS (Method 1): Rt 1.83min, m/z 172 [MH⁺].

c. 6-Fluoro-3-[1,4]oxazepan-4-yl-[1,2,4]triazolo[4,3-a]pyridine(Intermediate Fc)

A solution of Intermediate Fb (429 mg, 2.50 mmol) and homomorpholine(939 mg, 9.30 mmol) in NMP (10 mL) was heated in the microwave at 170°C. for 10 h. The cooled mixture was applied to an SCX-2 cartridge (70g), washing with methanol then eluting basic components with 0.4-2M NH₃in MeOH. The product containing fractions were combined and concentratedin vacuo. The residue was purified by FCC, using 0-12% [2M NH₃ in MeOH]in DCM, to give impure product. Further purified by FCC, using 0-12%MeOH in EtOAc gave Intermediate Fc (147 mg, 25%). LCMS (Method 3): Rt2.11 min, m/z 237 [MH⁺].

d.(1S,4R)-4-(3-[1,4]Oxazepan-4-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate F)

To a solution of Intermediate A (145 mg, 0.61 mmol) in DMF (3 mL) wasadded sodium hydride (60% dispersion in oil, 74 mg, 1.84 mmol). Themixture was stirred at RT for 15 min, then a solution of Intermediate Fc(100 mg, 0.614 mmol) in DMF (3 mL) was added and the mixture stirred at60° C. for 2.25 h. The cooled mixture was diluted with water andextracted with DCM (4×25 mL). The combined organics were dried andconcentrated in vacuo. The residue was purified by FCC, using 0-12% [2MNH₃ in MeOH] in DCM, to give Intermediate F (93 mg, 40%). LCMS (Method3): Rt 0.43 min, m/z 380 [MH⁺].

Intermediate G.(1S,4R)-4-[3-(4-Triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

a.[1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-piperidin-4-yl]-methanol(Intermediate Ga)

A solution of Intermediate Fb (593 mg, 3.45 mmol) and4-piperidinemethanol (1.59 g, 13.8 mmol) in NMP (10 mL) was heated inthe microwave at 170° C. for 3 h. The cooled mixture was applied to anSCX-2 cartridge (70 g), washing with methanol then eluting basiccomponents with 0.4-2 M NH₃ in MeOH. Product containing fractions werecombined and concentrated in vacuo. The residue was purified by FCC,using 0-15% MeOH in EtOAc, to give Intermediate Ga (481 mg, 56%). LCMS(Method 3): Rt 2.12 min, m/z 251 [MH⁺].

b.6-Fluoro-3-(4-triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(Intermediate Gb)

To a solution of Intermediate Ga (470 mg, 1.88 mmol) and Et₃N (390 μL,2.82 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethanesulfonate (607 μL, 2.26 mmol) and the mixture stirred at RT for 0.5 h.The mixture was washed with sat. aqueous NaHCO₃ solution, dried andconcentrated in vacuo. The residue was purified by FCC, using 0-100%EtOAc in cyclohexane, then 10% MeOH in EtOAc, to give Intermediate Gb(565 mg, 74%). LCMS (Method 3): Rt 5.21 min, m/z 407 [MH⁺].

c.(1S,4R)-4-[3-(4-Triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate G)

To a solution of Intermediate A (223 mg, 1.37 mmol) in DMF (3 mL) wasadded sodium hydride (60% dispersion in oil, 168 mg, 4.20 mmol) and themixture stirred at RT for 15 min. A solution of Intermediate Gb (555 mg,1.37 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for1.75 h. The cooled mixture was diluted with water and extracted with DCM(5×20 mL). The combined organics were dried and concentrated in vacuo.The residue was purified by FCC, using 0-14% [2M NH₃ in MeOH] in DCM, togive Intermediate G (344 mg, 46%). LCMS (Method 3): Rt 3.29 min, m/z 550[MH⁺].

Intermediate Hd.[5-tert-Butyl-2-(2-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester

a. (3-Amino-4-fluoro-phenyl)-methanol (Intermediate Ha)

4-Fluoro-3-nitrobenzyl alcohol (3.17 g, 18.5 mmol) was suspended inEtOH, and a slurry of palladium on carbon (10 wt %, 317 mg) in EtOH wasadded. The flask was sealed with a septum, evacuated, and a H₂ filledballoon was introduced via syringe and the reaction was stirred at RTovernight. The reaction mixture was then filtered through a pad ofCelite, washed with EtOH and the filtrates concentrated in vacuo toafford a oil which upon scratching crystallised to give the titlecompound (2.56 g, 98%). ¹H NMR (300 MHz, CDCl₃): 4.57 (2H, s), 6.63-6.71(1H, m), 6.77-6.84 (1H, m), 6.90-7.00 (1H, dd, J=8.2, 11.0 Hz). No OH orNH signals observed.

b. (4-Fluoro-3-hydrazino-phenyl)-methanol (Intermediate Hb)

A solution of Intermediate Ha (1.00 g, 7.10 mmol) in concentrated HCl(10 mL) was cooled to −5° C. in an acetone/dry ice bath, and whilestirring, a solution of NaNO₂ (513 mg, 7.40 mmol) in H₂O (2 mL) wasadded dropwise over 5 min. The reaction was stirred for 5 min, then asolution of SnCl₂ (2.96 g, 15.6 mmol) in concentrated HCl (4 mL) wasadded dropwise, ensuring the internal temperature did not exceed 0° C.After stirring for 40 min, 4N NaOH solution was added to adjust the pHto 14 (˜75 mL). The reaction mixture was then extracted three times withEtOAc, and the organic extracts combined, dried over MgSO₄, andconcentrated in vacuo to afford the title compound (866 mg, 78%). ¹H NMR(300 MHz, d₆-DMSO): 4.77 (2H, bs), 5.18 (2H, d, J=5.4 Hz), 5.85 (1H, t,J=5.6 Hz), 7.27-7.34 (2H, m), 7.68 (1H, dd, J=8.3, 12.1 Hz), 7.90 (1H,dd, J=2.0, 8.6 Hz).

c. [3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-4-fluoro-phenyl]-methanol(Intermediate Hc)

4,4-Dimethyl-3-oxopentanenitrile (694 mg, 5.55 mmol) and Intermediate Hb(866 mg, 5.55 mmol) were suspended in EtOH (25 mL) and refluxed for 72h. The reaction was cooled, concentrated in vacuo and partitionedbetween H₂O and EtOAc. The organic layer was separated, and the aqueousextracted with EtOAc. The combined organic extracts were dried overMgSO₄, concentrated in vacuo and subjected to FCC, eluting with 0-30%EtOAc/DCM, to afford the title compound (857 mg, 59%). LCMS (Method 3):Rt 2.35 min, m/z 264.3 [MH⁺]. ¹H NMR (300 MHz, CDCl₃): 1.31 (9H, s),1.87 (2H, bs), 3.67 (1H, bs), 4.67 (2H, s), 5.55 (1H, s), 7.18 (1H, dd,J=8.5, 10.3 Hz), 7.3-7.37 (1H, m), 7.52 (1H, dd, J=2.3, 7.4 Hz).

d.[5-tert-Butyl-2-(2-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Hd)

To an ice cooled solution of Intermediate He (737 mg, 2.80 mmol) inEtOAc (7 mL) and 1N NaOH solution (7 mL) was added 2,2,2-trichloroethylchloroformate (652 mg, 424 μL, 3.08 mmol) dropwise, and the ice bathremoved and the reaction allowed to warm to RT. After 90 min, thereaction was partitioned between H₂O and EtOAc; the organic layer wasseparated, and the aqueous layer extracted with EtOAc. The combinedorganic extracts were dried over MgSO₄ and concentrated in vacuo toafford an orange oil, which crystallised on scratching to give the titlecompound (1.2 g, 98%). LCMS (Method 3): Rt 3.95 min, m/z 438.2 [MH⁺]. ¹HNMR (300 MHz, CDCl₃): 1.35 (9H, s), 4.71 (2H, s), 4.77 (2H, s), 6.42(1H, s), 7.20-7.28 (1H, m), 7.38-7.45 (1H, m), 7.53-7.58 (1H, m).

Intermediate Ie.{5-tert-Butyl-2-[2-fluoro-5-(2-hydroxyethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2 trichloro-ethyl ester

a. 4-Fluoro-3-hydrazino-phenol (Intermediate Ia)

The title compound was prepared in an analogous manner to the proceduredescribed for Intermediate Hb starting from 3-amino-4-fluorophenol (2.00g, 15.7 mmol) to afford a solid (1.38 g, 62%). ¹H NMR (300 MHz,d₆-DMSO): 3.93 (2H, br s), 5.9 (1H, dt, J=3.2, 8.8 Hz), 6.41 (1H, s),6.57 (1H, dd, J=3.0, 7.6 Hz), 6.72 (1H, dd, J=8.6, 11.9 Hz), 8.9 (1H,s).

b. 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-4-fluoro-phenol (IntermediateIb)

The title compound was prepared in an analogous manner to the proceduredescribed for Intermediate He starting from Intermediate Ia (1.38 g 9.70mmol) (737 mg, 30%). ¹H NMR (300 MHz, CDCl₃): 1.33 (9H, s), 3.77 (2H,bs), 5.54 (1H, s), 6.61-6.69 (1H, m), 6.93 (1H, t, J=9.6 Hz), 7.02 (1H,dd, J=3.0, 6.3 Hz).

c.5-tert-Butyl-2-{2-fluoro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate Ic)

To an ice cooled solution of Intermediate Ib (737 mg, 2.96 mmol),2-(tetrahydro-2H-pyran-2-yloxy)ethanol (648 mg, 602 μL, 4.43 mmol) andtriphenylphosphine (1.55 g, 5.91 mmol) in anhydrous THF (250 mL) wasadded dropwise diisopropyl azodicarboxylate (1.20 g, 1.16 mL, 5.91mmol), and the reaction allowed to warm to RT and stirred for 18 h. Thereaction mixture was concentrated in vacuo, and subjected to FCC,eluting with 0-10% EtOAc/cyclohexane, and the product fractionscombined, concentrated in vacuo and subjected again to FCC, eluting with0-10% Et₂O/DCM, to afford the title compound (1.74 g). LCMS (Method 3):Rt 3.31 min, m/z 378.3 [MH⁺].

d. 2-[3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-4-fluoro-phenoxy]-ethanol(Intermediate Id)

Intermediate Ic was suspended in MeOH (5 mL) and applied to a 10 g SCX-2SPE cartridge and washed with MeOH. The product was eluted with 2M NH₃in MeOH and the basic eluent concentrated in vacuo to afford the titlecompound (411 mg, 37%). LCMS (Method 3): Rt 2.47 min, m/z 294.3 [MH⁺].

e.{5-tert-Butyl-2-[2-fluoro-5-(2-hydroxyethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2 trichloro-ethyl ester (Intermediate Ie)

To an ice cooled solution of Intermediate Id (411 mg, 1.40 mmol) inEtOAc (3.5 mL) and 1N NaOH solution (3.5 mL) was added2,2,2-trichloroethyl chloroformate (327 mg, 212 μL, 1.54 mmol) dropwise,and the ice bath removed and the reaction allowed to warm to RT. After 2h, a further 0.5 eq of 2,2,2-trichloroethyl chloroformate was added andthe reaction continued for a further 1 h. The reaction was partitionedbetween H₂O and EtOAc. The organic layer was separated, and the aqueousextracted with EtOAc. The combined organic extracts were dried overMgSO₄, concentrated in vacuo and subjected to FCC, eluting with 0-50%EtOAc/cyclohexane, to afford the title compound (246 mg, 37%). LCMS(Method 3): Rt 3.97 min, m/z 468.2 [MH⁺]. ¹H NMR (300 MHz, CDCl₃): 1.35(9H, s), 3.92-4.00 (2H, m), 4.06-4.12 (2H, m), 4.78 (2H, s), 6.40 (1H,s), 6.75 (1H, br s), 6.95 (1H, dt, J=3.5, 9.0 Hz), 7.08 (1H, dd, J=3.0,6.0 Hz), 7.17 (1H, t, J=9.4 Hz).

Intermediate Jb.[5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-carbamic acid2,2,2-trichloro-ethyl ester

a. 5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-ylamine(Intermediate Ja)

A black solution of 3,4-dimethylphenyl hydrazine hydrochloride (Apollo,1.73 g, 10.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.38 g, 11.0mmol) in EtOH (20 mL) was stirred at reflux for 5 h. The cooled solutionwas concentrated in vacuo, redissolved in diethyl ether (20 mL) andwashed with aqueous NaOH solution (1M, 20 mL). The aqueous was extractedwith diethyl ether (2×20 mL), then the combined organics washed withbrine (20 mL), dried (Na₂SO₄), filtered and concentrated in vacuo toleave the title compound (2.18 g, 90%). LCMS (Method 3): Rt 2.75 min,m/z 244 [MH⁺].

b. [5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-carbamic acid2,2,2-trichloro-ethyl ester (Intermediate Jb)

To a solution of Intermediate Ja (487 mg, 2.00 mmol) in EtOAc (5 mL) andaqueous NaOH solution (1M, 5.0 mL, 5.0 mmol) at RT was added2,2,2-trichloroethyl chloroformate (0.303 mL, 2.20 mmol) and theresulting mixture stirred for 90 min. The aqueous layer was extractedwith EtOAc (10 mL), then the combined organics washed with brine (10mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Triturationwith pentane/diethyl ether (2:1, 30 mL), and drying in vacuo affordedthe title compound (446 mg, 53%). LCMS (Method 3): Rt 4.70 min, m/z 418,420 [MH⁺].

Intermediate K.[5-tert-Butyl-2-(2,5-dimethyl-phenyl)-2H-pyrazol-3-yl]-carbamic acid2,2,2-trichloro-ethyl ester

The title compound was prepared starting from 2,5-dimethylphenylhydrazine hydrochloride using analogous procedures to those describedfor Intermediate Jb. LCMS (Method 3): Rt 4.68 min, m/z 418, 420 [MH⁺].

Intermediate L.[5-tert-Butyl-2-(2,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-carbamic acid2,2,2-trichloro-ethyl ester

The title compound was prepared starting from 2,4-dimethylphenylhydrazine using analogous procedures to those described for IntermediateJb. LCMS (Method 3): Rt 4.00 min, m/z 418, 420 [MH⁺].

Intermediate Md.[5-tert-Butyl-2-(4-chloro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester

a. (5-Amino-2-chloro-phenyl)-methanol (Intermediate Ma)

To a solution of (2-chloro-5-nitrophenyl)methanol (5.00 g, 26.7 mmol) inEtOAc (100 mL) was added water (2.41 mL, 134 mmol) followed by tin(II)chloride (12.7 g, 67.0 mmol). The solution was stirred at RT for 21 h,then additional tin(II) chloride (5.06 g, 26.7 mmol) was added, and themixture heated at 50° C. for 2 h, and then at 70° C. for 3 h. The cooledmixture was slowly basified with 1N sodium hydroxide solution (˜300 mL).The suspension was filtered through Celite, washing with EtOAc. Theaqueous layer was extracted with EtOAc (3×100 mL), then the combinedorganics washed with brine, dried over MgSO₄, and concentrated in vacuoto give the title compound (3.92 g, 93%). LCMS (Method 3): Rt 0.98 min,m/z 158 [MH⁺].

b. (2-Chloro-5-hydrazino-phenyl)-methanol (Intermediate Mb)

To a suspension of Intermediate Ma (3.90 g, 24.8 mmol) in concentratedhydrochloric acid (30 mL) at 0° C. was added, slowly, a solution ofsodium nitrite (2.07 g, 30.0 mmol) in water (10 mL). The mixture wasstirred at 0° C. for 1.25 h, then a solution of tin(II) chloride (11.8g, 62.0 mmol) in water (5 mL) and concentrated hydrochloric acid (20 mL)was added slowly. The mixture was stirred at 0° C. for 1.5 h, then wasdiluted with water and basified with NaOH (˜25 g). EtOAc was added, thenthe mixture filtered through Celite, and the filter-cake washed withEtOAc. The aqueous layer was extracted with EtOAc (3×100 mL), then thecombined organics were dried, and concentrated in vacuo to give thetitle compound (3.57 g, 84%). LCMS (Method 3): Rt 1.38 min, no massdata. ¹H NMR (300 MHz, d₆-DMSO): 3.96 (2H, s), 4.45 (2H, d, J=5.5 Hz),5.21 (1H, t, J=5.5 Hz), 6.66 (1H, dd, J=8.6, 2.8 Hz), 6.82 (1H, s), 6.98(1H, d, J=2.8 Hz), 7.06 (1H, d, J=8.6 Hz).

c. [5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenyl]-methanolhydrochloride (Intermediate Mc)

A mixture of Intermediate Mb (3.55 g, 20.6 mmol),4,4-dimethyl-3-oxopentanenitrile (2.57 g, 20.6 mmol) and concentratedhydrochloric acid (1.72 mL, 20.6 mmol) in ethanol (55 mL) was stirred atreflux for 3.5 h then cooled to RT and concentrated in vacuo. Theresidue was triturated with cyclohexane (3×100 mL), then suspended incyclohexane (150 ml) and filtered. The solid was washed with diethylether (2×25 mL), air dried, then dried in vacuo at 45° C. to give thetitle compound as a pale orange powder (6.30 g, 97%). LCMS (Method 3):Rt 2.68 min, m/z 280 [MH⁺].

d.[5-tert-Butyl-2-(4-chloro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Md)

To a mixture of Intermediate Mc (3.16 g, 10.0 mmol) in EtOAc (60 mL) and1N NaOH solution (28.0 ml, 28.0 mmol) at 0° C. was added2,2,2-trichloroethyl chloroformate (1.92 mL, 14.0 mmol) and the mixturestirred for 2 h. Solid NaOH (0.40 g, 10.0 mmol) and 2,2,2-trichloroethylchloroformate (0.69 mL, 5.00 mmol) were added sequentially, and themixture stirred at 0° C. for 1.5 h. The organic layer was washed withbrine, dried and concentrated in vacuo. The residue was suspended withcyclohexane, the solid filtered, washed with cyclohexane, air dried,then dried in vacuo at 50° C. to give the title compound (2.74 g, 60%).LCMS (Method 3): Rt 4.13 min, m/z 454, 456, 458 [MH⁺].

Intermediate Nc.{5-tert-Butyl-2-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester

a. 5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-fluoro-phenol (IntermediateNa)

To a solution of 3-(tert-butyl)-1H-pyrazol-5-amine (1.00 g, 7.20 mmol)in toluene (13 mL) was added 5-bromo-2-fluorophenol (1.51 g, 7.90 mmol),potassium carbonate (2.08 g, 15.1 mmol),(1S,2S)—N,N′-bis-methyl-1,2-cyclohexane-diamine (0.20 g, 1.40 mmol) thencopper (I) iodide (0.07 g, 0.36 mmol). The mixture was degassed thenheated at 150° C. for 1 h using microwave irradiation. Another portionof copper (I) iodide (0.07 g, 0.36 mmol) was added and the reactionmixture heated at 150° C. for a further 1 h using microwave irradiation.The mixture was diluted with EtOAc and water and the phases separated.The aqueous layer was then extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried (Na₂SO₄), filtered andevaporated in vacuo to give an impure solid. The residue was partitionedbetween DCM and water and the phases separated. The organic layer wasevaporated in vacuo and the residue was purified by FCC, using 0-5% MeOHin DCM. Further purification by FCC, using 0-25% EtOAc in DCM, gave thetitle compound as an orange gum (1.25 g, 70%). LCMS (Method 3): Rt 2.33min, m/z 250.3 [MH⁺].

b.5-Tert-butyl-2-{4-fluoro-3-[2-(tetrahydro-pyran-2-yloxy-ethoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate Nb)

A solution of Intermediate Na (1.25 g, 5.00 mmol) in dry THF (35 mL) wastreated with 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (1.02 mL, 7.50 mmol)and triphenylphosphine (2.63 g, 10.0 mmol) then cooled to 0° C.Diisopropyl azodicarboxylate (1.97 mL, 10.0 mmol) was added dropwisethen the mixture was stirred at RT for 2.75 h. The mixture was treatedwith water (0.45 mL) then evaporated in vacuo. The residue was purifiedby FCC, using 0-10% EtOAc in DCM. Further purification by FCC, using0-40% EtOAc in cyclohexane gave the title compound as pale orangeviscous oil (1.44 g, 76%). LCMS (Method 3): Rt 3.32 min, m/z 378.4[MH⁺].

c.{5-tert-Butyl-2-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Nc)

To a solution of Intermediate Nb (1.44 g, 3.80 mmol) in EtOAc (20 mL)was added 1N aqueous NaOH solution (6.80 mL, 6.80 mmol) followed by2,2,2-trichloroethylchloroformate (0.58 mL, 4.20 mmol). The reaction wasstirred for 2.5 h then diluted with EtOAc and water. The aqueous layerwas then extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was purified by FCC, using 0-40% EtOAc in cyclohexane, to givethe title compound as a colorless oil (0.51 g, 28%). LCMS (Method 3): Rt4.06, m/z 468, 470 [MH⁺].

Intermediate Ob.{5-tert-Butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester

a.5-tert-Butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-ylamine(Intermediate Oa)

To a stirred solution of5-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol (WO2007/091152,which is incorporated herein by reference; 200 mg, 0.75 mmol), 2-Nmorpholino ethanol (137 μL, 1.13 mmol) and Ph₃P (394 mg, 1.50 mmol) inTHF (7.5 mL) at 0° C. was added DEAD (236 μL, 1.50 mmol). After 1 h, thereaction mixture was diluted with water and extracted with DCM. Thecombined organics were dried and concentrated in vacuo. The residue waspurified by FCC, using 0-5% [2M NH₃ in MeOH] in DCM, to give the titlecompound (228 mg, 80%). LCMS (Method 3): Rt 2.28 min, m/z 379 [MH⁺].

b.{5-tert-Butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Ob)

To a solution of Intermediate Oa (228 mg, 0.60 mmol) and DIPEA (236 μL,1.35 mmol) in THF (7.5 mL) at 0° C. was added 2,2,2-trichloroethylchloroformate (124 μL, 0.90 mmol) and the mixture stirred for 1.25 h.The reaction mixture was diluted with water and extracted with DCM. Thecombined organics were washed with brine, dried and concentrated invacuo. The residue was purified by FCC, using 0-5% [2M NH₃ in MeOH] inDCM, to give the title compound (330 mg, 99%). LCMS (Method 3): Rt 3.15min, m/z 553, 555, 557 [MH⁺].

Intermediate Pd.{5-tert-Butyl-2-[4-methyl-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester

a. 5-Hydrazino-2-methyl-phenol hydrochloride salt (Intermediate Pa)

To an ice cold slurry of 4-amino-2-hydroxytoluene (6.22 g, 50.0 mmol),ice (10.0 g) and hydrochloric acid (37% aqueous, 15.0 mL) was added anice-cold solution of sodium nitrite (3.49 g, 50.0 mmol) in water (10.0mL) over 30 min. The resultant slurry was added over 30 min to anice-cold slurry of tin (II) chloride (25.3 g, 133 mmol) in water (30.0mL) and hydrochloric acid (37% aqueous, 30.0 mL) and the reactionstirred overnight. The mixture was cooled in an ice/water bath and thesolid collected by filtration, washing with ice-cold cyclohexane. Theresidue was dried in vacuo at 50° C. to give the title compound (waterretained, 11.1 g). ¹H NMR (300 MHz, d₄-MeOD): 2.12 (3H, s), 6.38 (1H,dd, J=2.3, 8.0 Hz), 6.44 (1H, d, J=2.3 Hz), 7.02 (1H, d, J=8.1 Hz).

b. 5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-methyl-phenol (IntermediatePb)

4,4-Dimethyloxo-pentanenitrile (7.50 g, 60.0 mmol) was added to asolution of Intermediate Pa (wet 11.1 g) in MeOH (200 mL) and thereaction stirred overnight. The reaction was then heated to 60° C.overnight, then cooled, and evaporated in vacuo. The residue wassuspended in EtOAc and stirred for 15 min, then the solid collected byfiltration. The filtrate was evaporated in vacuo then purified by FCC,using 0-10% [2M NH₃ in MeOH] in DCM, and combined with the filteredsolid to give the title compound (5.78 g, 47%). LCMS (Method 4): Rt2.07, m/z 240.6 [MH⁺].

c.5-tert-Butyl-2-[4-methyl-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-ylamine(Intermediate Pc)

DIAD (788 μL, 4.02 mmol) was added to a solution of Intermediate Pb (500mg, 2.01 mmol), 4-(2-hydroxyethylmorpholine) (367 μL, 3.02 mmol) andPh₃P (1.05 g, 4.02 mmol) in THF/DMF (2:1, 12.0 mL). The reaction washeated to 60° C. overnight then cooled and partitioned between EtOAc andwater. The aqueous layer was then extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried (MgSO₄), filteredand evaporated in vacuo. The residue was purified by FCC, using 0-5% [2MNH₃ in MeOH] in DCM, to give the title compound (400 mg, 56%). LCMS(Method 1): Rt 1.81, m/z 359.1 [MH⁺].

d.{5-tert-Butyl-2-[4-methyl-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Pd)

To an ice-cold solution of Intermediate Pc (148 mg, 0.41 mmol) in THF(4.0 mL) was added DIPEA (287 μL, 1.65 mmol) followed by2,2,2-trichloroethylchloroformate (114 μL, 0.83 mmol). The reaction wasstirred overnight, then partitioned between EtOAc and water. The aqueouslayer was then extracted with EtOAc (3×). The combined organic layerswere washed with brine, dried (MgSO₄), filtered and evaporated in vacuo.The residue was taken up in DCM/EtOAc (1:1, 20.0 mL) and NH₂-silica(11.0 g) added. The mixture was stirred for 2 h then filtered and thefiltrate evaporated in vacuo. The residue was purified by FCC, using0-5% [2M NH₃ in MeOH] in DCM, to give the title compound (163 mg, 74%).LCMS (Method 1): Rt 2.88, m/z 533, 535 [MH⁺].

Intermediate Qc.{5-tert-Butyl-2-[3-chloro-5-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester

a.5-tert-Butyl-2-{3-chloro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate Qa)

To a solution of Intermediate 62b (550 mg, 2.07 mmol), Ph₃P (1.09 g,4.14 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.42 mL, 3.10mmol) in THF (10 mL) was added DEAD (0.65 mL, 4.10 mmol) and thesolution stirred at RT for 10 min. Water (0.1 mL) was added, then themixture concentrated in vacuo to ˜3 mL volume. FCC, using 5-35% EtOAc incyclohexane, gave the title compound (733 mg, 90%). LCMS (Method 3): Rt4.05 min, m/z 394 [MH⁺].

b.(5-tert-Butyl-2-{3-chloro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Qb)

To a solution of Intermediate Qa (732 mg, 1.86 mmol) in aq. NaOHsolution (1M, 2.8 mL) and EtOAc (5 mL) at RT was added2,2,2-trichloroethyl chloroformate (0.28 mL, 2.00 mmol) and the mixturestirred at RT for 2 h. The aqueous layer was extracted with EtOAc (10mL), then the combined organics washed with brine (5 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to leave a oil (1.04 g).FCC, using 5-25% EtOAc in cyclohexane, gave the title compound (714 mg,67%). LCMS (Method 3): Rt 4.99 min, m/z 568, 570 [MH⁺].

c.{5-tert-Butyl-2-[3-chloro-5-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Qc)

A solution of Intermediate Qb (518 mg, 0.910 mmol) and PPTS (686 mg,2.73 mmol) in MeOH (15 mL) was stirred at 40° C. for 2 h. The cooledsolution was concentrated in vacuo, suspended in water (5 mL) and sat.aq. NaHCO₃ solution (5 mL), and then extracted with DCM (10 mL). Theorganics were passed through a hydrophobic frit and concentrated invacuo to leave a solid. Residual pyridine was removed with tolueneazeotropes (2×20 mL) to leave the title compound (428 mg, 97%). LCMS(Method 3): Rt 4.30 min, m/z 484, 486 [MH⁺].

Intermediate Rd.{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester

a. (2-Chloro-5-iodo-phenyl)-acetic acid methyl ester (Intermediate Ra)

A dark red solution of (2-chlorophenyl)acetic acid methyl ester (TCI,1.53 mL, 10.0 mmol), NIS (2.36 g, 10.5 mmol) and AuCl₃ (152 mg, 0.50mmol) in DCE (25 mL) was stirred at reflux under Ar for 18 h. Thesolution was cooled to RT, NIS (563 mg, 2.50 mmol) added and the purplesolution stirred at reflux for 2 h. The solution was cooled to RT,filtered through Celite and the filtercake washed with DCM. The combinedorganics were concentrated in vacuo to leave a solid that was dissolvedin diethyl ether (50 mL), washed with water (2×50 mL), brine (50 mL),dried (Na₂SO₄), filtered and concentrated in vacuo to leave a purple oil(3.0 g). FCC, using 2-7% EtOAc in cyclohexane, gave the title compoundas a clear oil (1.07 g, 34%) and a clear oil (mixed fractions, 814 mg,26%). LCMS (Method 3): Rt 4.09 min, m/z 311 [MH⁺].

b. 2-(2-Chloro-5-iodo-phenyl)-ethanol (Intermediate Rb)

To a solution of Intermediate Ra (810 mg, 2.61 mmol) in dry THF (10 mL)at 0° C. under N₂ was added LiAlH₄ (198 mg, 5.22 mmol) and the greysuspension stirred at RT for 90 min. Water (0.2 mL), 15% aqueous NaOHsolution (0.2 mL) and water (0.6 mL) were added sequentially (CARE: gasevolution and exotherm) and the mixture stirred at RT for 1 h. Thesuspension was diluted with THF (25 mL), filtered through Celite and thefiltercake washed with diethyl ether (50 mL). Water (50 mL) was added tothe combined organics and the mixture shaken. The aqueous was extractedwith diethyl ether (50 mL), then the combined organics washed with brine(50 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to leave aclear oil (499 mg). FCC, using 10-30% EtOAc in cyclohexane, gave thetitle compound as a clear oil (236 mg, 32%). LCMS (Method 3): Rt 3.61min, m/z 265 [M-H₂O+H⁺].

c. 2-[5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenyl]-ethanol(Intermediate Rc)

A suspension of Intermediate Rb (236 mg, 0.835 mmol),3-tert-butyl-1H-pyrazole-5-amine (Fluorochem, 122 mg, 0.88 mmol),copper(I) iodide (8.00 mg, 0.04 mmol),trans-N,N′-dimethylcyclohexane-1,2-diamine (23.8 mg, 0.17 mmol) andK₂CO₃ (242 mg, 1.75 mmol) in degassed toluene (1 mL) was stirred at 100°C. under Ar for 3 h, and then heated to 150° C. for 5 h using microwaveirradiation. The cooled solution was partitioned between EtOAc (10 mL),water (5 mL) and concentrated aqueous ammonia (5 mL). The aqueous layerwas extracted with EtOAc (10 mL), then the combined organics washed withwater (10 mL), brine (10 mL), dried (Na₂SO₄), filtered and concentratedin vacuo to leave a oil (305 mg). FCC, using 20-45% EtOAc incyclohexane, gave the title compound as an opaque sticky gum (129 mg,53%). LCMS (Method 3): Rt 2.80 min, m/z 294 [MH⁺].

d.{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Rd)

A biphasic mixture of Intermediate R^(C) (129 mg, 0.44 mmol) and2,2,2-trichloroethyl chloroformate (66.5 μL, 0.48 mmol) in EtOAc (1 mL)and aqueous NaOH solution (1M, 0.66 mL, 0.66 mmol) was stirred at RT for1 h. The mixture was diluted with EtOAc (20 mL), then the organicswashed with brine (10 mL), dried (Na₂SO₄), filtered and concentrated invacuo to leave a oil. FCC, using 10-35% EtOAc in cyclohexane, gave thetitle compound (143 mg, 69%). LCMS (Method 3): Rt 4.26 min, m/z 468,470, 472 [MH⁺].

Intermediate Sb.[5-tert-Butyl-2-(3-chloro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester

a. 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-5-chloro-benzoic acid ethylester (Intermediate Sa)

3-(Tert-butyl)-1H-pyrazol-5-amine (1.10 g, 7.90 mmol), potassiumcarbonate (2.29 g, 16.6 mmol), and copper (I) iodide (75.0 mg, 1.58mmol) were weighed into a microwave vial and purged with argon.3-Bromo-5-chloro-benzoic acid ethyl ester (2.50 g, 9.49 mmol) was thenadded, followed by trans-N,N′-dimethylcyclohexane-diamine (225 mg, 1.58mmol) and the reaction vessel purged with argon. The reagents were thensolvated with toluene (8 mL), and then degassed with argon, sealed andsubjected to microwave irradiation (135° C., 6 h). The reaction mixturewas filtered through Celite, concentrated in vacuo and purified by FCC,eluting with 0-10% EtOAc/cyclohexane, to afford the title compound (489mg, 19%). LCMS (Method 3) Rt 4.26 min, 322.1 [MH⁺].

b.[5-tert-Butyl-2-(3-chloro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Sb)

Intermediate Sa (489 mg, 1.52 mmol) was suspended in IMS (15 mL) andsodium borohydride (143 mg, 3.80 mmol) was added portionwise and thereaction stirred at RT. After 18 h, a further 1.0 eq of sodiumborohydride was added and the mixture heated to 50° C. After 6 h, thereaction was cooled, partitioned between H₂O and DCM and passed througha phase separator, and the organics concentrated in vacuo. The resultantproduct (413 mg, 1.48 mmol) was then suspended in an EtOAc/H₂O mixture(3:1, 15 mL), and sodium hydroxide (159 mg, 3.99 mmol) added. Whilestirring at RT, 2,2,2-trichlorethyl chloroformate (244 μL, 1.77 mmol)was added dropwise. After 45 min, the reaction was partitioned betweenH₂O and DCM. The organic layer was separated, dried over MgSO₄,concentrated in vacuo and purified by FCC, eluting with 0-50%EtOAc/cyclohexane, to afford the title compound (656 mg, 97%). LCMS(Method 3) Rt 4.29 min, 455.9, 457.9 [MH⁺].

Intermediate Td.(5-tert-Butyl-2-{2-chloro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamicacid 2,2,2-trichloro-ethyl ester

a. 4-Chloro-3-hydrazino-phenol hydrochloride salt (Intermediate Ta)

A solution of sodium nitrite (2.07 g, 30.0 mmol) in water (6.0 mL) wasadded dropwise to an ice cold slurry of 3-amino-4-chlorophenol (4.30 g,30.0 mmol) and hydrochloric acid (37% aqueous, 9.0 mL) and the mixturestirred for 45 min. Tin (II) chloride (15.4 g, 81.0 mmol) in water (18.0mL) and hydrochloric acid (37% aqueous, 18.0 mL) was added dropwise andthe reaction stirred overnight. The mixture was cooled in an ice/waterbath, diluted with water and neutralised by addition of NaOH (1M aq).The aqueous layer was then extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried (MgSO₄), filtered andevaporated in vacuo. The residue was passed through an acidicion-exchange cartridge (SCX-2), washing with methanol and eluting with2M ammonia in methanol. The basic fraction was evaporated in vacuo thenpurified by FCC, using 3-10% [2M NH₃ in MeOH] in DCM, to give the titlecompound (1.30 g, 27%). ¹H NMR (300 MHz, d₆-DMSO): 4.12 (2H, br s), 6.03(1H, dd, J=8.5, 2.9 Hz), 6.26 (1H, s), 6.63 (1H, d, J=2.7 Hz), 6.93 (1H,d, J=8.5 Hz), 9.22 (1H, s).

b 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-4-chloro-phenol (IntermediateTb)

4,4-Dimethyloxo-pentanenitrile (1.15 g, 9.23 mmol) was added to asolution of Intermediate Ta (1.20 g, 7.69 mmol) in MeOH (20 mL) andhydrochloric acid (37% aqueous, 0.2 mL) and the reaction was heated to65° C. overnight, then cooled and evaporated in vacuo. The residue wastaken up in EtOAc and water and the aqueous layer was then extractedwith EtOAc (3×). The combined organic layers were washed with brine,dried (MgSO₄), filtered and evaporated in vacuo. The residue waspurified by FCC, using 0-100% EtOAc in cyclohexane, to give the titlecompound (1.35 g, 66%). LCMS (Method 4): Rt 2.21 min, m/z 266 [MH⁺].

c.5-tert-Butyl-2-{2-chloro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate Tc)

DEAD (799 μL, 5.09 mmol) was added dropwise to a solution ofIntermediate Tb (675 mg, 2.55 mmol),2-(tetrahydro-2H-pyran-2-yloxy)ethanol (518 μL, 3.83 mmol) and Ph₃P(1.33 g, 5.09 mmol) in THF (11.0 mL). The reaction was stirred over theweekend and then partitioned between EtOAc and water. The aqueous layerwas then extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried (MgSO₄), filtered and evaporated in vacuo. Theresidue was purified by FCC, using 0-70% EtOAc in cyclohexane, to givean inseparable mixture of title compound and Intermediate Tb. This wasresubmitted to the same reaction and purification conditions to give thetitle compound (150 mg, 35%). LCMS (Method 4): Rt 2.94 min, m/z 394[MH⁺].

d.(5-tert-Butyl-2-{2-chloro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Td)

To an ice-cold solution of Intermediate Tc (350 mg, 0.89 mmol) inEtOAc/water (2:1, 4.5 mL) was added sodium hydroxide (71.0 mg, 1.78mmol) followed by 2,2,2-trichloroethylchloroformate (147 μL, 1.07 mmol).The reaction was stirred for 90 min and then partitioned between EtOAcand water. The aqueous layer was then extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried (MgSO₄), filteredand evaporated in vacuo. The residue was purified by FCC, using 0-70%EtOAc in cyclohexane, to give the title compound (396 mg, 78%). LCMS(Method4): Rt 4.44 min, m/z 568, 570 [MH⁺].

Intermediate TeD.1-{5-tert-Butyl-2-[2-chloro-5-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

Pyridinium para-toluene sulfonate (76.0 mg, 0.31 mmol) was added to asolution of Intermediate (TdD) (118 mg, 0.15 mmol) in MeOH (2.0 mL). Thereaction was heated to 55° C. for 90 min then cooled and partitionedbetween EtOAc and water. The aqueous layer was then extracted with EtOAc(3×). The combined organic layers were washed with brine, dried (MgSO₄),filtered and evaporated in vacuo to give the title compound (83.0 mg,77%). LCMS (Method 4): Rt 3.21 min, m/z 699 [MH⁺].

Intermediate Ub.[5-tert-Butyl-2-(3-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester

a. [3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-5-fluoro-phenyl]-methanol(Intermediate Ua)

Degassed toluene (sparged with argon for 25 mins, 10.0 mL) was added toa mixture of 3-bromo-5-fluorobenzylalcohol (1.00 g, 4.88 mmol),3-tert-butyl-H-pyrazole-5-amine (678 mg, 4.88 mmol), copper (I) iodide(46.0 mg, 0.24 mmol) and potassium carbonate (1.41 g, 10.2 mmol).Trans-N,N′-dimethylcyclohexanediamine (154 μL, 0.98 mmol) was added andthe reaction heated to 150° C. for 18 h using microwave irradiation. Themixture was partitioned between EtOAc and water. The aqueous layer wasthen extracted with EtOAc (3×). The combined organic layers were washedwith brine, dried (MgSO₄), filtered and evaporated in vacuo. The residuewas purified by FCC, using 0-100% EtOAc in cyclohexane, to give thetitle compound (307 mg, 24%). LCMS (Method 4): Rt 2.34 min, m/z 264[MH⁺].

b[5-tert-Butyl-2-(3-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Ub)

To a solution of Intermediate Ua (307 mg, 1.17 mmol) in EtOAc/water(2:1, 6.0 mL) was added sodium hydroxide (93.0 mg, 2.33 mmol) followedby 2,2,2-trichloroethylchloroformate (193 μL, 1.40 mmol). The reactionwas stirred for 3 h then partitioned between EtOAc and water. Theaqueous layer was then extracted with EtOAc (3×). The combined organiclayers were washed with brine, dried (MgSO₄), filtered and evaporated invacuo to give the title compound (486 mg, 94%). LCMS (Method 4): Rt 3.78min, m/z 438, 440 [MH⁺].

Intermediate Ve.4-{5-[3-tert-Butyl-5-(2,2,2-trichloro-ethoxycarbonylamino)-pyrazol-1-yl]-2-chloro-phenoxy}-piperidine-1-carboxylicacid 2-trimethylsilanyl-ethyl ester

a. 4-(2-Chloro-5-iodo-phenoxy)-piperidine-1-carboxylic acid tert-butylester (Intermediate Va)

2-Chloro-5-iodophenol (2.50 g, 9.83 mmol), tert-butyl4-hydroxy-1-piperidinecarboxylate (2.97 g, 14.7 mmol) andtriphenylphosphine (5.15 g, 19.6 mmol), were suspended in THF (50 mL)and cooled to 0° C. Diethyl azodicarboxylate (3.08 mL, 19.6 mmol) wasthen added dropwise, the reaction was stirred under a N₂ atmosphere for18 h. The reaction was then partitioned between H₂O and EtOAc. Theorganic layer was separated, washed with saturated brine, dried overMgSO₄, concentrated in vacuo and subjected to FCC, eluting with 0-50%EtOAc/cyclohexane, to afford the title compound (3.43 g, 80%). (Method3): Rt 4.98 min, m/z 337.9 [M-BOC⁺].

b. 4-(2-Chloro-5-iodo-phenoxy)-piperidine (Intermediate Vb)

Trifluoroacetic acid (10 mL) was added to a solution of Intermediate Va(3.43 g, 7.84 mmol) in DCM (30 mL). After 10 min, the reaction wasconcentrated in vacuo, and loaded on to a 50 g SCX-2 SPE cartridge. Thecartridge was washed with DCM, then MeOH and the product eluted with 2MNH₃ in MeOH solution and the basic eluent concentrated in vacuo toafford the title compound (3.03 g, 100%). LCMS (Method 3) Rt 2.36 min,m/z 337.9 [MH⁺].

c. 4-(2-Chloro-5-iodo-phenoxy)-piperidine-1-carboxylic acid2-trimethylsilanyl-ethyl ester (Intermediate Vc)

To a stirred solution of Intermediate Vb (3.02 g, 8.94 mmol) andtriethylamine (2.49 mL, 17.9 mmol) in THF (45 mL) was added1-[2-(trimethylsilyl)ethoxy-carbonyloxy]pyrrolidin-2,5-dione (2.78 g,10.7 mmol) and heated to reflux under a N₂ atmosphere. After 1 h, thereaction was cooled, partitioned between H₂O and DCM, and the organiclayer separated, dried over MgSO₄, concentrated in vacuo and subjectedto FCC, eluting with 0-50% EtOAc/cyclohexane, to afford the titlecompound (4.26 g, 99%). LCMS (Method 3) Rt 5.34 min.

d.4-[5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenoxy]-piperidine-1-carboxylicacid 2-trimethylsilanyl-ethyl ester (Intermediate Vd)

A microwave vial was charged with 3-tert butyl-1H-pyrazole-5-amine (1.03g, 7.39 mmol), copper (I) iodide (70.3 mg, 0.37 mmol) and potassiumcarbonate (2.14 g, 15.5 mmol) and the vial sealed with a septum,evacuated and purged with argon.Trans-N,N′-dimethylcyclohexane-1,2-diamine (210 mg, 1.48 mmol) was thenadded, then a solution of Intermediate Vc (4.26 g, 8.86 mmol) in toluene(7.5 mL, degassed with argon) was added, and the reaction was subjectedto microwave irradiation (150° C. for 1 h). The reaction mixture wasthen filtered through Celite, and the filtrate concentrated in vacuo.Purification by FCC, eluting with 0-60% EtOAc/cyclohexane, to afford thetitle compound (2.41 g, 66%). LCMS (Method 3) Rt 4.68 min, m/z 493, 495[MH⁺].

e.4-{5-[3-tert-Butyl-5-(2,2,2-trichloro-ethoxycarbonylamino)-pyrazol-1-yl]-2-chloro-phenoxy}-piperidine-1-carboxylicacid 2-trimethylsilanyl-ethyl ester (Intermediate Ve)

2,2,2-Trichloroethyl chloroformate (760 μL, 5.58 mmol) was added to astirred solution of Intermediate Vd (2.29 g, 4.65 mmol) and NaOH (602mg, 15.1 mmol) in EtOAc (4.5 mL) and H₂O (11.5 mL) at RT. After 1 h, afurther 0.2 eq. of 2,2,2-trichloroethyl chloroformate was added. After afurther 15 min, the reaction was partitioned between H₂O and EtOAc. Theorganic layer was separated, dried over MgSO₄ and concentrated in vacuoto afford the title compound (3.56 g, 100%). LCMS (Method 3) Rt 5.39min, m/z 666, 668 [MH⁺].

Intermediate Wc.(5-tert-Butyl-2-{3-fluoro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamicacid 2,2,2-trichloro-ethyl ester

a. 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-5-fluoro-phenol (IntermediateWa)

Degassed toluene (sparged with argon for 25 mins, 10.0 mL) was added toa mixture of 3-bromo-5-fluorophenol (1.00 g, 5.23 mmol),3-tert-butyl-H-pyrazole-5-amine (728 mg, 5.23 mmol), copper (I) iodide(50.0 mg, 0.26 mmol) and potassium carbonate (1.52 g, 11.0 mmol).Trans-N,N′-dimethylcyclohexanediamine (165 μL, 1.05 mmol) was added andthe reaction heated to 150° C. for 3.5 h using microwave irradiation.The mixture was partitioned between EtOAc and water. The aqueous layerwas then extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried (MgSO₄), filtered and evaporated in vacuo. Theresidue was purified by FCC, using 0-75% EtOAc in cyclohexane, to givethe title compound (488 mg, 37%). LCMS (Method 4): Rt 2.49 min, m/z 250[MH⁺].

b5-tert-Butyl-2-{3-fluoro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate Wb)

DEAD (614 μL, 3.92 mmol) was added dropwise to a solution ofIntermediate Wa (488 mg, 1.96 mmol),2-(tetrahydro-2H-pyran-2-yloxy)ethanol (397 μL, 2.94 mmol) and Ph₃P(1.03 g, 3.92 mmol) in THF (10.0 mL). The reaction was then stirred overthe weekend, then partitioned between EtOAc and water. The aqueous layerwas then extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried (MgSO₄), filtered and evaporated in vacuo. Theresidue was purified by FCC, using 0-60% EtOAc in cyclohexane, to givethe title compound (635 mg, 86%). LCMS (Method 1): Rt 3.50 min, m/z 378[MH⁺].

c(5-tert-Butyl-2-{3-fluoro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate We)

To a solution of Intermediate Wb (488 mg, 1.96 mmol) in EtOAc/water(2:1, 7.5 mL) was added sodium hydroxide (135 mg, 3.37 mmol) followed by2,2,2-trichloroethylchloroformate (278 μL, 2.02 mmol). The reaction wasstirred for 2 h then partitioned between EtOAc and water. The aqueouslayer was then extracted with EtOAc (3×). The combined organic layerswere washed with brine, dried (MgSO₄), filtered and evaporated in vacuoto give the title compound (740 mg, 80%). LCMS (Method 4): Rt 4.56 min,m/z 552, 554 [MH⁺].

Intermediate WdC.1-{5-tert-Butyl-2-[3-fluoro-5-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

Pyridinium para-toluene sulfonate (199 mg, 0.79 mmol) was added to asolution of Intermediate WcC (315 mg, 0.40 mmol) in MeOH (4.0 mL). Thereaction was heated to 55° C. for 2 h then cooled and partitionedbetween EtOAc and water. The aqueous layer was then extracted with EtOAc(3×). The combined organic layers were washed with brine, dried (MgSO₄),filtered and evaporated in vacuo to give the title compound (192 mg,68%). LCMS (Method 4): Rt 3.63 min, m/z 711 [MH⁺].

Intermediate WdB.1-{5-tert-Butyl-2-[3-fluoro-5-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

Pyridinium para-toluene sulfonate (163 mg, 0.65 mmol) was added to asolution of Intermediate WcB (253 mg, 0.32 mmol) in MeOH (3.5 mL). Thereaction was heated to 55° C. for 3 h then cooled and partitionedbetween EtOAc and water. The aqueous layer was then extracted with EtOAc(3×). The combined organic layers were washed with brine, dried (MgSO₄),filtered and evaporated in vacuo. The residue was purified by FCC, using3-10% [2M NH₃ in MeOH] in DCM, to give the title compound (200 mg, 90%).LCMS (Method 4): Rt 3.44 min, m/z 697 [MH⁺].

Intermediate Xc.{5-tert-Butyl-2-[4-cyano-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester

a. 4-Bromo-2-(2-hydroxy-ethoxy)-benzonitrile (Intermediate Xa)

4-Bromo-2-hydroxybenzonitrile (1.00 g, 5.05 mmol), ethylene carbonate(467 mg, 5.30 mmol) and potassium carbonate (348 mg, 2.52 mmol) weresuspended in DMF (2.00 mL) and heated to 125° C. for 4.5 h. The mixturewas partitioned between EtOAc and water. The aqueous layer was thenextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried (MgSO₄), filtered and evaporated in vacuo. The residue waspurified by FCC, using 0-100% EtOAc in cyclohexane to give the titlecompound (686 mg, 56%). ¹H NMR (300 MHz, d₄-MeOD): 3.92 (2H, t, J=4.7Hz), 4.21 (2H, t, J=4.7 Hz), 7.26 (1H, dd, J=8.2, 1.7 Hz), 7.44 (1H, d,J=1.6 Hz), 7.53 (1H, d, J=8.2 Hz).

b.4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-(2-hydroxy-ethoxy)-benzonitrile(Intermediate Xb)

Degassed toluene (sparged with argon for 25 mins, 10.0 mL) was added toa mixture of Intermediate Xa (1.30 g, 5.37 mmol),3-tert-butyl-1H-pyrazole-5-amine (821 mg, 5.90 mmol), copper (I) iodide(51.0 mg, 0.27 mmol) and potassium carbonate (1.56 g, 11.3 mmol).Trans-N,N′-dimethylcyclohexanediamine (169 μL, 1.07 mmol) was added andthe reaction heated to 150° C. for 15 h using microwave irradiation. Themixture was partitioned between EtOAc and water. The aqueous layer wasthen extracted with EtOAc (3×). The combined organic layers were washedwith brine, dried (MgSO₄), filtered and evaporated in vacuo. The residuewas purified by FCC, using 0-100% EtOAc in cyclohexane, to give thetitle compound (490 mg, 32%). LCMS (Method 4): Rt 2.72 min, m/z 301[MH⁺].

c.{5-tert-Butyl-2-[4-cyano-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Xc)

To a solution of Intermediate Xb (490 mg, 1.63 mmol) in EtOAc/water(2:1, 24.0 mL) was added sodium hydroxide (131 mg, 3.27 mmol) followedby 2,2,2-trichloroethylchloroformate (270 μL, 1.96 mmol). The reactionwas stirred for 4 h then further sodium hydroxide (90.0 mg, 2.25 mmol)and 2,2,2-trichloroethylchloroformate (135 μL, 0.98 mmol) were added.The reaction was stirred overnight, then partitioned between EtOAc andwater. The aqueous layer was then extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried (MgSO₄), filteredand evaporated in vacuo. The residue was purified by FCC, using 0-60%EtOAc in cyclohexane, to give the title compound (557 mg, 72%). LCMS(Method 4): Rt 3.74 min, m/z 474, 476 [MH⁺].

Intermediate Yd.{5-tert-Butyl-2-[4-fluoro-3-(2-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester

a. 2-(5-Amino-2-fluoro-phenyl)-ethanol (Intermediate Ya)

Borane-THF complex (1M, 11.8 mL, 11.8 mmol) was added to a solution of(5-amino-2-fluoro-phenyl)-acetic acid (1.00 g, 5.91 mmol) in dry THF (10mL), under argon, over 20 min. Once the effervescence had ceased, thereaction mixture was heated to 50° C. for 2 h. The mixture was left tocool and then concentrated in vacuo. The residue was re-dissolved in DCM(25 mL) and treated with MeOH (2 mL). The mixture was stirred vigorouslyand then concentrated in vacuo. The residue was dissolved in MeOH (25mL) and re-concentrated in vacuo. The residue was purified by FCC, using0-10% [2M NH₃ in MeOH] in DCM, to afford the title compound (0.54 g,59%). LCMS (Method 3): Rt: 0.41 min, m/z 156 [MH⁺].

b. 2-(2-Fluoro-5-hydrazino-phenyl)-ethanol (Intermediate Yb)

Intermediate Ya (0.54 g, 3.48 mmol) was dissolved in concentratedaqueous HCl (5 mL) and cooled to −5° C. To this was added a solution ofsodium nitrite (0.25 g, 3.65 mmol), in water (0.75 mL), dropwise.Stirring continued for 5 min, before a solution of tin (II) chloride(1.45 g, 7.66 mmol) in concentrated aqueous HCl (2.2 mL) was added. Thereaction mixture was stirred just below 0° C. for 40 min and thenbasified using aqueous NaOH (4M, 30 mL). The mixture was then stirred atRT for 1.5 h. This was extracted into EtOAc (3×50 mL). The combinedorganics were washed with brine (2×50 mL), dried (MgSO₄), filtered andconcentrated in vacuo to afford the title compound (302 mg, 51%). LCMS(Method 3): Rt: 0.42 min, m/z 171 [MH⁺].

c. 2-[5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-fluoro-phenyl]-ethanol(Intermediate Yc)

A mixture of 4,4-dimethyl-3-oxo-pentanenitrile (200 mg, 1.60 mmol) andIntermediate Yb (300 mg, 1.76 mmol) and concentrated aqueous HCl (0.02mL) in IMS (5 mL) was refluxed for 18 h. The reaction mixture was leftto cool and concentrated in vacuo. The residue was purified by FCC,using 0-10% [2M NH₃ in MeOH] in DCM, to afford the title compound (350mg, 79%). LCMS (Method 3): Rt: 0.44/2.04/2.26 min, m/z 278 [MH⁺].

d.{5-tert-Butyl-2-[4-fluoro-3-(2-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Yd)

A solution of Intermediate Yc (345 mg, 1.24 mmol) in EtOAc (3.5 mL) wastreated with aqueous NaOH (1M, 2.24 mmol), followed by2,2,2-trichloroethyl chloroformate (205 μL, 1.49 mmol) and the reactionmixture was stirred at RT for 1 h. The mixture was partitioned betweenEtOAc (10 mL) and water (10 mL). The layers were separated and theaqueous layer was extracted with a further EtOAc (10 mL). The combinedorganic layers were washed with water (10 mL) and brine (10 mL), dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified byFCC, using 0-50% EtOAc in cyclohexane, to afford the title compound (472mg, 84%). LCMS (Method 3): Rt 4.09 min, m/z 452/454 [MH⁺].

Intermediate Zb.[5-tert-Butyl-2-(4-fluoro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester

a. [5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-fluoro-phenyl]-methanol(Intermediate Za)

A microwave vial (25 mL) was charged with3-(tert-butyl)-1H-pyrazol-5-amine (1.05 g, 7.54 mmol),5-bromo-2-fluorobenzyl alcohol (1.70 g, 8.29 mmol) copper (I) iodide(72.0 mg, 5 mol %), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.21 g,1.47 mmol) and potassium carbonate (2.19 g, 15.8 mmol) under argon.Xylenes (12 mL) was added and the mixture degassed (5×), the vial sealedand then heated to 135° C. overnight. After cooling, the mixture waspartitioned between EtOAc (100 mL) and water (100 mL), separated and theaqueous layer extracted with EtOAc (100 mL). The organic extracts werecombined and washed (water and brine), then dried (MgSO₄) andconcentrated. The residue was purified by FCC, eluting withDCM/cyclohexane (1:1) and then 0-5% [2M NH₃ in MeOH] in DCM, to give aresidue (0.85 g). The product was triturated (DCM/pentane) and air driedto afford the title compound (0.46 g). LCMS (Method 3): Rt 2.23 min, m/z264 [MH⁺]. ¹H NMR (300 MHz, CDCl₃): 1.31 (9H, s), 4.77 (2H, br s), 5.52(1H, s), 7.11 (1H, t, J=9.0 Hz), 7.45 (1H, m), 7.66 (1H, m).

b.[5-tert-Butyl-2-(4-fluoro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate Zb)

2,2,2-Trichloroethyl chloroformate (0.26 mL, 1.89 mmol) was added to astirred mixture of Intermediate Za (0.46 g, 1.75 mmol) and NaOH (aq 1M,3.2 mL, 3.20 mmol) in EtOAc (4 mL). Stirring was continued at RT for 1 hand the mixture was diluted with water, and then extracted with EtOAc(2×25 mL). The combined extracts were washed (water and brine), thendried (MgSO₄) and concentrated to give the title compound. LCMS (Method3): Rt 4.05 min, m/z 438 [MH⁺].

Intermediate 53cE.1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

a.1-(5-tert-Butyl-2-{4-chloro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 53bE)

A solution of Intermediate 53b (299 mg, 0.525 mmol), Intermediate E (182mg, 0.50 mmol) and DIPEA (0.11 mL, 0.63 mmol) in dry dioxane (10 mL) wasstirred at 75° C. for 18 h. The cooled solution was concentrated invacuo, suspended in water (10 mL) and extracted with DCM (2×10 mL). Thecombined organics were passed through a hydrophobic frit andconcentrated in vacuo to leave the title compound (451 mg). LCMS (Method3): Rt 3.22 min, m/z 783 [MH⁺].

b.1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 53cE)

A solution of Intermediate 53bE (assume 0.50 mmol) and pyridiniump-toluenesulfonate (377 mg, 1.50 mmol) in MeOH was stirred at 40° C. for16 h. The solution was concentrated in vacuo, suspended in water (10 mL)and sat. aq. NaHCO₃ solution (10 ml), and then extracted with DCM (2×10mL). The combined organics were passed through a hydrophobic frit andconcentrated in vacuo. FCC, using 2-6% MeOH in DCM, gave the titlecompound (149 mg, 43%). LCMS (Method 3): Rt 2.85 min, m/z 699 [MH⁺].

General Procedure for Table 1—Urea Formation.

The compounds synthesized in Table 1 were prepared according to thefollowing general procedure: A mixture of Intermediate LHS (1.0 eq),Intermediate RHS (1.0 eq) and DIPEA (1.2-1.5 eq.) in a suitable solvent(for example 1,4-dioxane, 2-methyltetrahydrofuran or THF) was heated(60-80° C.) for a suitable time until the reaction was complete (e.g.5-24 h). The reaction mixture was cooled, concentrated in vacuo andsubjected to chromatographic purification methods described herein.

TABLE 1 Urea Formation. Interm. Interm. Interm. used used No. (LHS)(RHS) Intermediate Structure NMR (δ) LCMS Inter- me- diate HdC Hd C

(300 MHz, CDCl₃): 0.64 (6H, t, J = 6.8 Hz), 1.34 (9H, s), 1.36-1.63 (3H,m), 1.69-1.97 (3H, m), 1.98- 2.27 (4H, m), 3.15-3.32 (2H, m), 4.59 (2H,s), 5.00-5.11 (1H, m), 5.17- 5.23 (1H, m), 5.87-5.95 (1H, m), 6.36 (1H,s), 6.94 (1H, dd, J = 2.2, 9.9 Hz), 6.99-7.11 (2H, m), 7.20-7.38 (5H,m), 7.39-7.45 (1H, d, J = 9.9 Hz), 7.48 (1H, dd, J = 2.0, 7.4 Hz), 7.66(1H, d, J = 1.6 Hz). (Method 3): Rt 3.85 min, m/z 681.5 [MH⁺].1-[5-tert-Butyl-2-(2-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate HdB Hd B

(Method 3): Rt 3.61 min, m/z 667.4 [MH⁺].1-[5-tert-Butyl-2-(2-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3- ((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate IeB Ie B

(Method 3): Rt 3.63 min, m/z 697.5 [MH⁺].1-{5-tert-Butyl-2-[2-fluoro-5-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate IeC Ie C

(Method 3): Rt 3.85 min, m/z 711.3 [MH⁺].1-{5-tert-Butyl-2-[2-fluoro-5-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate NcB Nc B

(Method 3): Rt 3.69 mins, m/z 697 [MH⁺].1-{5-tert-Butyl-2-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate NcC Nc C

(Method 3): Rt 3.90 mins, m/z 711 [MH⁺].1-{5-tert-Butyl-2-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate QcB Qc B

(300 MHz, CDCl₃): 0.85 (3H, d, J 6.2), 1.33 (9H, s), 1.39-1.48 (2H, m),1.57- 1.67 (2H, m), 1.71-1.80 (2H, m), 1.89-2.13 (3H, m), 2.20-2.30 (1H,m), 2.76-2.84 (1H, m), 2.95- 3.02 (1H, m), 3.11-3.20 (1H, m), 3.83 (2H,t, J 4.3), 3.96 (2H, t, J 4.3), 5.08 (1H, td, J 8.4, 5.2), 5.19 (1H, t,J 3.9), 6.40 (1H, s), 6.64 (1H, t, J 2.0), 6.87 (1H, d, J 2.3), 6.90(1H, d, J 2.3), (Method 3): Rt 3.91 min, m/z 713 [MH⁺].1-{5-tert-Butyl-2-[3-chloro-5-(2-hydroxy- 7.04 (1H, t, J 2.0),ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)- 7.14 (1H, t, J 1.8),4-[3-((S)-2-methyl-piperidin-1-yl)- 7.20-7.30 (4H, m),[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4- 7.38-7.41 (2H, m),tetrahydro-naphthalen-1-yl}-urea 8.11 (1H, br s). OH signal missing.Inter- me- diate RdD Rd D

(300 MHz, d₆-DMSO): 1.28 (9H, s), 1.57-1.67 (2H,m), 1.68-1.77 (3H, s),1.82-2.00 (3H, s), 2.02- 2.18 (2H, m), 2.91 (2H, t, J 6.9), 3.14 (4H, t,J 5.1), 3.65 (2H, apparent q, J 6.4), 4.77 (1H, t, J 5.3), 4.81 (1H, m),5.55 (1H, t, J 4.2), 6.34 (1H, s), 7.05 (1H, d, J 8.5), 7.16 (1H, dd, J9.8, 2.1), 7.24-7.40 (5H, m), 7.50 (1H, d, J 2.6), 7.54 (1H, d, J 8.6),7.59-7.64 (2H, m), 8.13 (1 H, s). (Method 3): Rt 3.69 min, m/z 683[MH⁺]. 1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]- urea Inter- me- diate TdDTd D

(Method 4): Rt 3.73 mins, m/z 783 [MH⁺]. 1-(5-tert-Butyl-2-{2-chloro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea Inter- me- diate UbC Ub C

(Method 4): Rt 3.63 mins, m/z 681 [MH⁺].1-[5-tert-Butyl-2-(3-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate VeD Ve D

(Method 3): Rt 4.92 mins, m/z 882.1 [MH⁺].4-[5-(3-tert-Butyl-5-{3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureido}-pyrazol-1-yl)-2-chloro-phenoxy]- piperidine-1-carboxylic acid2-trimethylsilanyl- ethyl ester Inter- me- diate WcC Wc C

(Method 4): Rt 4.22 mins, m/z 795 [MH⁺]. 1-(5-tert-Butyl-2-{3-fluoro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}- urea Inter- me- diate UbB UbB

(Method 4): Rt 3.38 mins, m/z 667 [MH⁺].1-[5-tert-Butyl-2-(3-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3- ((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate WcB Wc B

(Method 4): Rt 3.99 mins, m/z 781 [MH⁺]. 1-(5-tert-Butyl-2-{3-fluoro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate XcB Xc B

(Method 9): Rt 3.25 mins, m/z 704 [MH⁺]. 1-{5-tert-Butyl-2-[4-cyano-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate RdC Rd C

(Method 3): Rt 4.09 mins, m/z 711/713 [MH⁺]. 1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethyl)- phenyl]-2H-pyrazol-3-yl}-{(1S,4R)4-[3- ((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate RdB Rd B

(Method 3): Rt 3.87 mins, m/z 697/699 [MH⁺].1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate MdB Md B

(300 MHz, d₆-DMSO): 0.91 (3H, d, J 6.3), 1.28 (9H, s), 1.51 (2H, m),1.61-2.18 (8H, m), 2.90 (1H, ddd, J 12.2, 8.5, 4.3), 3.16 (1H, dt, J12.1, 4.3), 3.25-3.31 (1H, m), 4.61 (2H, d, J 5.5), 4.80 (1H, td, J 8.4,5.7), 5.50-5.56 (2H, m), 6.34 (1H, s), 7.04 (1H, d, J 8.6), 7.19 (1H,dd, J 9.9, 2.1), 7.25-7.44 (5H, m), 7.52 (1H, d, J 8.5), 7.64 (1H, d, J9.9), 7.69 (2H, m), 8.14 (1 H, s). (Method 3): Rt 3.83 min, m/z 683[MH⁺]. 1-[5-tert-Butyl-2-(4-chloro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3- ((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate MdC Md C

(300 MHz, d₆-DMSO): 0.60 (3H, d, J 6.0), 0.63 (3H, d, J 6.1), 1.28 (9H,s), 1.37-1.62 (3H, m), 1.66- 1.97 (5H, m), 2.00-2.13 (2H, m), 3.17 (2H,m), 4.61 (2H, d, J 5.5), 4.81 (1H, td, J 8.5, 5.6), 5.52 (1H, m), 5.54(1H, t, J 5.7), 6.33 (1H, s), 7.04 (1H, d, J 8.6), 7.21 (1H, dd, J 9.9,2.2), 7.25-7.36 (4H, m), 7.42 (1H, dd, J 8.5, 2.6), 7.52 (1H, d, J 8.5),7.65-7.69 (2H, m), 7.89 (1H, d, J 2.1), 8.15 (1H, s). (Method 3): Rt4.05 min, m/z 697 [MH⁺]. 1-[5-tert-Butyl-2-(4-chloro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate YdB Yd B

(400 MHz, CDCl₃): 0.86 (3H, d, J = 6.1 Hz), 1.35 (9H, s), 1.38-1.53 (2H,m), 1.56-1.84 (4H, m), 1.86-1.99 (1H, m), 2.00- 2.26 (3H, m), 2.48-2.61(1H, m), 2.64-2.77 (1H, m), 2.79-2.92 (1H, m), 2.96-3.06 (1H, m), 3.13-3.26 (1H, m,), 3.31- 3.45 (1H, m,), 3.52- 3.63 (1H, m), 5.04-5.15 (1H,m), 5.15-5.21 (1H, m), 6.49 (1H, s), 6.79-6.97 (2H, m), 7.09- 7.34 (5H,m, obscured by solvent), 7.35-7.47 (3H, m).1-{5-tert-Butyl-2-[4-fluoro-3-(2-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea Inter- me- diate ZbB Zb B

(Method 3): Rt 3.68 mins, m/z 667 [MH⁺].1-[5-tert-Butyl-2-(4-fluoro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3- ((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

General Procedure for Table 2. Mesylate Formation.

The compounds synthesised in Table 2 were prepared according to thefollowing general procedure: the intermediate obtained in Table A (1.0eq.) and DIPEA (3.0 eq.) were suspended in DCM, and methanesulfonylchloride (1.2 eq.) added and stirred at RT. After 1 h, the reactionmixture was partitioned with H₂O and DCM, the organic layer separated,dried, and concentrated in vacuo and used directly in the followingstep.

TABLE 2 Mesylate Formation. Intermediate Intermediate used Structure ofproduct No. LCMS HdC

HeC (Method 3): Rt 4.09 min, m/z 759.5 [MH⁺]. HdB

HeB (Method 3): Rt 3.87 min, m/z 685.5 [MH⁺]. IeB

IfB (Method 3): Rt 3.89 min, m/z 775.4 [MH⁺]. IeC

IfC (Method 3): Rt 4.10 min, m/z 789.3 [MH⁺]. Example 82

MeD (Method 3): Rt 3.89 min, m/z 746.9 [MH⁺]. Example 53

53d (Method 3): Rt 3.89 min, m/z 777.1/779.1 [MH⁺]. NeB

NdB (Method 3): Rt 3.91 mins, m/z 775 [MH⁺]. NeC

NdC (Method 3): Rt 4.12 mins, m/z 789 [MH⁺]. QeB

QdB (Method 3): Rt 4.11 min, m/z 791 [MH⁺]. RdD

ReD (Method 3): Rt 3.92 min, m/z 761 [MH⁺]. SbD

SeD (Method 3): Rt 3.96 min, m/z 747, 749 [MH⁺]. TeD

7fD (Method 1): Rt 3.54 mins, m/z 777 [MH⁺]. UbC

UeC (Method 1): Rt 3.96 mins, m/z 759 [MH⁺]. WdC

WeC (Method 4): Rt 3.89 mins, m/z 789 [MH⁺]. UbB

UeB (Method 4): Rt 3.65 mins, m/z 745 [MH⁺]. WdB

WeB (Method 4): Rt 3.65 mins, m/z 776 [MH⁺]. XcB

XdB (Method 4): Rt 3.58 mins, m/z 782 [MH⁺]. RdB

ReB (Method 3): Rt 4.06 mins, m/z 775.777 [MH⁺]. RdC

ReC (Method 3): Rt 4.28 mins, m/z 789/791 [MH⁺]. YdB

YeB (Method 3): Rt: 3.94 mins, m/z 759 [MH⁺]. 53cE

53dE (Method 3): Rt 3.07 min, m/z 777 [MH⁺]. MdB

MeB (Method 3): Rt: 4.03 min, m/z 761 [MH⁺]. MdC

MeC (Method 3): Rt 4.22 min, m/z 775 [MH⁺]. ZbB

ZeB (Method 3): Rt 3.90 mins, m/z 745 [MH⁺].

General Procedure for Table 3. Amine Displacement.

The compounds synthesised in Table 3 were prepared according to thefollowing general procedure: the intermediate obtained in Table B andthe corresponding amine were suspended in a suitable solvent (THF, MeOH)and heated (60-80° C.) for a suitable time until the reaction wascomplete (5-24 h). The reaction mixture was cooled, concentrated invacuo and subjected to chromatographic purification methods describedherein.

TABLE 3 Amine Displacement. Ex No. Amine (equivalents used) IntermediateExample Structure NMR (400 MHz) δ LCMS 1 Pyrrolidine (3.0 eq.) HeC

(d₆-DMSO): 0.55 (3H, d, J = 6.3 Hz), 0.58 (3H, d, J = 6.3 Hz), 1.22 (9H,s), 1.33 (3H, m), 1.58-1.70 (6H, m), 1.72-1.84 (2H, m), 1.85- 1.95 (1H,m), 1.96-2.07 (2H, m), 3.07-3.19 (3H, m), 3.27 (3H, m, obscured bywater), 3.61 (2H, s), 4.72-4.81 (1H, m), 5.48 (1H, t, J = 4.3 Hz), 6.29(1H, s), 6.93 (1H, d, J = 8.4 Hz), 7.13-7.17 (1H, dd, J = 2.2, 9.7 Hz),7.17-7.24 (2H, m), 7.25-7.32 (2H, m), 7.33-7.39 (2H, m), 7.40-7.46 (1H,m), 7.59-7.65 (1H, m), 7.83 (1H, d, J = 1.3 Hz), 8.00 (1H, s), 8.10(0.4H, s) (Method 5): Rt 3.83 min, m/z 734.4 [MH⁺]. 21-Methyl-piperazine (3.0 eq.) HeC

(d₆-DMSO): 0.55 (3H, d, J = 6.3 Hz), 0.58 (3H, d, J = 6.3 Hz), 1.22 (9H,s), 1.32-1.57 (3H, s), 1.60- 1.70 (2H, m), 1.71-1.84 (2H, m), 1.85-1.95(1H, m), 1.96-2.05 (2H, m), 2.06 (3H, s), 2.24 (4H, bs), 2.34 (4H, bs),3.06-3.20 (2H, m), 3.44 (2H, s), 4.72-4.81 (1H, m), 5.48 (1H, t, J = 4.3Hz), 6.29 (1H, s), 6.91 (1H, d, J = 8.4 Hz), 7.12- 7.17 (1H, dd, 2.2,9.7 Hz), 7.17- 7.24 (2H, m), 7.25-7.37 (4H, m), 7.37-7.43 (1h, m),7.61-7.64 (1H, m), 7.84 (1H, d, J = 1.3 Hz), 7.99 (1H, s). (Method 5):Rt 3.79 min, m/z 763.5 [MH⁺]. 3 Pyrrolidine (3.0 eq). HeB

(d₆-DMSO): 0.86 (3H, d, J = 6.2 Hz), 1.22 (9H, s), 1.42-1.51 (2H, m),1.57-1.69 (6H, m), 1.70-1.84 (3H, m), 1.84-1.94 (1H, m), 1.95- 2.08 (2H,m), 2.37-2.43 (4H, m), 2.80-2.91 (1H, m), 3.07-3.15 (2H, m), 3.56 (2H,s), 4.70-4.80 (1H, m), 5.47 (1H, t, J = 4.2 Hz), 6.29 (1H, s), 6.95 (1H,d, J = 8.7 Hz), 7.14 (1H, dd, J = 2.1, 9.9 Hz), 7.16-7.25 (2H, m),7.25-7.29 (1H, m), 7.29- 7.37 (3H, m), 7.38-7.45 (1H, m), 7.59 (1H, d, J= 9.7 Hz), 7.65 (1H, d, J = 1.6 Hz), 8.00 (1H, s), 8.16 (0.6H). (Method5): Rt 3.65 min, m/z 720.4 [MH⁺]. 4 1-Methyl-piperazine (3.0 eq.) HeB

(d₆-DMSO): 0.86 (3H, d, J = 6.4 1.22 (9H, s), 1.41-1.53 (2H, m),1.55-1.68 (2H, m), 1.69-1.84 (3H, m), 1.85-1.93 (1H, m), 1.95-2.10 (3H,m), 2.06 (3H, s), 2.24 (4H, bs), 2.34 (4H, bs), 2.82-2.90 (1H, m),3.07-3.15 (1H, m), 3.26 (3H, m, obscured by water), 3.44 (2H, s),4.71-4.80 (1H, m), 5.47 (1H, t, J = 4.6 Hz), 6.29 (1H, s), 6.91 (1H, d,J = 8.5 Hz), 7.13 (1H, dd, J = 2.2, 10.1 Hz), 7.16-7.21 (1H, m), 7.21-7.25 (1H, m), 7.25-7.29 (1H, m), 7.29-7.37 (3H, m), 7.37-7.43 (1H, m),7.56-7.61 (1H, m), 7.6 (1H, d, J = 1.4 Hz), 7.98 (1H, s). (Method 5): Rt3.62 min, m/z 749.4 [MH⁺]. 5 Dimethylamin, (2M solution in THF) IfB

(d₆-DMSO): 0.86 (3H, d, J = 6.4 Hz), 1.22 (9H, s), 1.41-1.52 (2H, m),1.56-1.68 (2H, m), 1.70-1.84 (3H, m), 1.85-1.94 (1H, m), 1.95- 2.10 (2H,m), 2.14 (6H, s), 2.55 (2H, t, J = 5.8 Hz), 2.82-2.90 (1H, m), 3.08-3.15(1H, m), 3.27 (1H, m, obscured by water), 4.02 (2H, t, J = 5.8 Hz,4.72-4.81 (1H, m), 5.47 (1H, t, J = 4.2 Hz), 6.29 (1H, s), 6.97-7.02(2H, m), 7.02-7.08 (1H, m), 7.14 (1H, dd, J = 2.2, 9.9 Hz), 7.18-7.25(2H, m), 7.26-7.35 (3H, m), 7.59 (1H, d, J = 9.8 Hz), 7.65 (1H, d, J =1.5 Hz), 8.01 (1H, s), 8.16 (0.66H, s) (Method 5): Rt 3.65 min, m/z724.4 [MH⁺]. 6 Dimethylamine, (2M solution in THF) IfC

(d₆-DMSO): 0.55 (3H, d, J = 6.3 Hz), 0.58 (3H, d, J = 6.3 Hz), 1.22 (9H,s), 1.33-1.57 (3H, m), 1.61- 1.70 (2H, m), 1.72-1.85 (2H, m), 1.85-1.95(1H, m), 1.98-2.06 (2H, m), 2.13 (6H, s), 2.55 (2H, t, J = 5.8 Hz),3.08-3.19 (3H, m), 3.30 (3H, m, obscured by water), 4.02 (2H, t, J = 5.8Hz), 4.73-4.82 (1H, m), 5.48 (1H, t, J = 4.4 Hz), 6.29 (1H, s),6.97-7.08 (3H, m), 7.15 (1H, dd, J = 2.2, 9.9 Hz), 7.18-7.24 (2H, m),7.25-7.34 (3H, m), 7.59- 7.64 (1H, m), 7.84 (1H, d, J = 1.8 Hz), 8.03(1, s), 8.22 (0.37H, s). (Method 5): Rt 3.82 min, m/z 738.4 [MH⁺]. 71-Methyl-piperazine (3,5 eq.) MeD

(d₆-DMSO): 1.28 (9H, s), 1.57-1.66 (2H, m), 1.68-1.77 (4H, m), 1.81-1.96 (2H, m), 1.99-2.16 (5H, m), 2.21-2.50 (8H, m), 3.10-3.17 (4H, m),3.57 (2H, br s), 4.76-4.84 (1H, m), 5.55 (1H, br t, J = 4.3 Hz), 6.33(1H, s), 6.96 (1H, d, J = 8.4 Hz), 7.16 (1H, dd, J = 2.2, 10.0 Hz),7.23-7.45 (5H, m), 7.55 (1H, d, J = 8.4 Hz), 7.58-7.63 (3H, m), 8.14(1H, br s). (Method 5): Rt 3.57 min, m/z 751.3 [MH⁺]. 8 Morpholine (3.5eq.) MeD

(d₆-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.76 (4H, m), 1.80-1.96 (2H, m), 1.99-2.16 (2H, m), 2.40-2.47 (4H, m), 3.10-3.17 (4H, m),3.51-3.61 (6H, m), 4.76-4.84 (1H, m), 5.54 (1H, br t, J = 4.3 Hz), 6.33(1H, s), 6.97 (1H, d, J 8.4), 7.16 (1H, dd, J = 2.0, 10.1 Hz), 7.21-7.46(5H, m), 7.56 (1H, d, J = 8.5 Hz), 7.59-7.64 (3H, m), 8.14 (1H, br s).(Method 5): Rt 3.58 min, m/z 738.3 [MH⁺]. 9 Dimethylamine (2M solutionin THF) 53d

(d₆-DMSO): 1.28 (9H, s), 1.57-1.66 (2H, m), 1.67-1.78 (4H, m), 1.79-1.97 (2H, m), 1.99-2.17 (2H, m), 2.19 (6H, s), 2.64 (2H, t, J = 5.7 Hz),3.11-3.17 (4H, m), 4.16 (2H, t, J = 5.6 Hz), 4.76-4.85 (1H, m), 5.55(1H, t, J = 4.3 Hz), 6.34 (1H, s), 7.05-7.18 (3H, m), 7.22-7.41 (5H, m),7.54 (1H, d, J = 8.4 Hz), 7.59-7.65 (2H, m), 8.15 (1H, br s). (Method5): Rt 3.53 mins, m/z 726.3 [MH⁺]. 10 Diethylamine (3.0 eq) 53d

d₆-DMSO): 0.92 (6H, t, J = 7.2 Hz), 1.28 (9H, s), 1.57-1.66 (2H, m),1.67-1.78 (4H, m), 1.79-1.97 (2H, m), 1.99-2.17 (2H, m), 2.51 (4H, q,under DMSO), 2.78 (2H, t, J = 5.8 Hz), 3.11-3.17 (4H, m), 4.11 (2H, t, J= 5.8 Hz), 4.77-4.85 (1H, m), 5.55 (1H, t, J = 4.3 Hz), 6.34 (1H, s),7.04-7.18 (3H, m), 7.23-7.41 (5H, m), 7.54 (1H, d, J = 8.4 Hz),7.59-7.64 (2H, m), 8.14 (1H, br s). (Method 5): Rt 3.68 mins, m/z 754.4[MH⁺]. 11 Piperidine (3.0 eq.) 53d

d₆-DMSO: 1.24-1.33 (11H, m), 1.37-1.46 (4H, m), 1.57-1.66 (2H, m),1.68-1.78 (4H, m), 1.79-1.97 (2H, m), 1.99-2.17 (2H, m), 2.36- 2.44 (4H,m), 2.62-2.70 (2H, m), 3.11-3.17 (4H, m), 4.17 (2H, t, J = 5.8 Hz),4.76-4.85 (1H, m), 5.53 (1H, t, J = 4.3 Hz), 6.34 (1H, s), 7.07-7.18(3H, m), 7.23-7.41 (5H, m), 7.53 (1H, d, J = 8.4 Hz), 7.59- 7.64 (2H,m), 8.17 (1H, br s). (Method 5): Rt 3.67 min, m/z 766.6 [MH⁺]. 12Pyrrolidine (3.0 eq.) 53d

d₆-DMSO: 1.28 (9H, s), 1.57-1.66 (6H, m), 1.68-1.78 (4H, m), 1.80- 1.97(2H, m), 1.98-2.16 (2H, m), 2.46-2.55 (presumed 4H, m, under DMSO),2.75-2.83 (2H, m), 3.11- 3.17 (4H, m), 4.17 (2H, t, J = 5.8 Hz),4.76-4.85 (1H, m), 5.55 (1H, t, J = 4.2 Hz), 6.34 (1H, s), 7.06-7.18(3H, m), 7.22-7.41 (5H, m), 7.54 (1H, d, J = 8.5 Hz), 7.59-7.64 (2H, m),8.15 (1H, br s). (Method 5): Rt 3.62 mins, m/z 752.5 [MH⁺]. 13Dimethylamine (2M solution in THF) NdB

(d₆-DMSO): 0.91 (3H, d, J = 6.2 Hz), 1.27 (9H, s), 1.45-1.56 (2H, m),1.62-1.72 (2H, m), 1.74-1.97 (4H, m), 2.00-2.18 (2H, m), 2.19 (6H, s),2.64 (2H, t, J = 5.7 Hz), 2.87-2.95 (1H, m), 3.12-3.20 (1H, m, obscuredby water), 3.27-3.35 (1H, m, obscured by water), 4.15 (2H, t, J = 5.6Hz), 4.78-4.85 (1H, m), 5.52 (1H, t, J = 4.3 Hz), 6.33 (1H, s),7.02-7.07 (1H, m), 7.09 (1H, d, J = 8.6 Hz), 7.18 (1H, dd, J = 9.7, 2.2Hz), 7.24-7.39 (6H, m), 7.64 (1H, d, J = 9.6 Hz), 7.69 (1H, d, J = 1.7Hz), 8.10 (1H, s), 8.17 (1H, s) (Method 5): Rt 3.63 mins, m/z 724.4[MH⁺]. 14 Dimethylamine (2M solution in THF) NdC

(d₆-DMSO): 0.60 (3H, d, J = 6.2 Hz), 0.63 (3H, d, J = 6.2 Hz), 1.27 (9H,s), 1.38-1.58 (3H, m), 1.67- 1.75 (2H, m), 1.77-1.98 (3H, m), 2.04-2.11(2H, m), 2.18 (6H, s), 2.63 (2H, t, J = 5.9 Hz), 3.12-3.23 (2H, m,obscured by water), 4.15 (2H, t, J = 5.8 Hz), 4.78-4.86 (1H, m), 5.53(1H, t, J = 4.1 Hz), 6.33 (1H, s), 7.02-7.07 (1H, m), 7.09 (1H, d, J =8.6 Hz), 7.20 (1H, dd, J = 9.8, 2.3 Hz), 7.23-7.28 (2H, m), 7.29-7.37(4H, m), 7.67 (1H, d, J = 10.0 Hz), 7.87 (1H, d, J = 2.0 Hz), 8.09 (1H,s), 8.17 (1H, s) (Method 5) Rt 3.80 mins, m/z 738.5 [MH⁺]. 15Dimethylamine (2M solution in THF) QdB

(400 MHz, d₆-DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.45-1.56(2H, m), 1.62-1.71 (2H, m), 1.75- 1.85 (2H, m), 1.86-1.94 (1H, m),2.00-2.08 (1H, m), 2.11-2.16 (1H, m), 2.19 (6H, s), 2.63 (2H, t, J = 5.7Hz), 2.90 (1H, ddd, J = 12.2, 9.3, 3.8 Hz), 3.16 (1H, dt, J = 11.5, 4.5Hz), 3.29-3.34 (1H, m), 4.12 (2H, t, J = 5.7 Hz), 4.81 (1H, m), 5.52(1H, t, J = 4.2 Hz), 6.32 (1H, s), 7.06 (1H, t, J = 2.1 Hz), 7.10 (1H,t, J = 2.1 Hz), 7.14 (1H, d, J = 8.7 Hz), 7.18-7.21 (2H, m), 7.25- 7.38(4H, m), 7.64 (1H, dd, J = 0.8, 9.8 Hz), 7.69 (1H, d, J = 2.1), 8.16(1H, s), 8.20 (1H, s). (Method 5): Rt 3.80 min, m/z 740.5 [MH⁺]. 16Morpholine (3.0 eq) ReD

(400 MHz, d₆-DMSO): 1.28 (9H, s), 1.58-1.64 (2H, m), 1.69-1.76 (4H, m),1.81-1.95 (2H, m), 1.99- 2.16 (2H, m), 2.41 (4H, t, J = 4.2 Hz),2.52-2.55 (2H, m), 2.90 (2H, dd, J = 6.4, 9.1 Hz), 3.14 (4H, t, J = 5.2Hz), 3.54 (4H, t, J = 4.5 Hz), 4.80 (1H, td, J = 8.5, 5.3 Hz), 5.54 (1H,t, J = 4.3 Hz), 6.33 (1H, s), 7.06 (1H, d, J = 8.5 Hz), 7.16 (1H, dd, J= 9.8, 2.2 Hz), 7.23-7.35 (3H, m), 7.37 (1H, d, J = 2.2 Hz), 7.40 (1H,d, J 2.6 Hz), 7.53 (1H, d, J = 8.6 Hz), 7.55 (1H, d, J = 2.5 Hz), 7.61(1H, dd, J = 0.9, 8.0 Hz), 7.63 (1H, s), 8.14 (1H, s). (Method 5): Rt3.55 min, m/z 752.5 [MH⁺]. 17 Dimethylamine (2M solution in THF) ReD

(d₆-DMSO): 1.28 (9H, s), 1.58-1.65 (2H, m), 1.68-1.78 (4H, m), 1.81-1.95 (2H, m), 2.00-2.15 (2H, m), 2.17 (6H, s), 2.45-2.49 (2H, m), 2.86(2H, dd, J = 8.8, 6.5 Hz), 3.14 (4H, t, J = 5.2 Hz), 4.80 (1H, td, J =8.5, 5.6 Hz), 5.54 (1H, t, J = 4.3 Hz), 6.33 (1H, s), 7.06 (1H, d, J =8.6 Hz), 7.16 (1H, dd, J = 2.0, 10.0 Hz), 7.24-7.40 (6H, m), 7.52 (1H,d, J = 1.8 Hz), 7.54 (1H, d, J = 4.3 Hz), 7.61 (1H, dd, J = 7.3, 0.9Hz), 7.63 (1H, s), 8.14 (1H, s). (Method 5): Rt 3.53 min, m/z 710.5[MH⁺]. 18 Piperidine (3.0 eq) SeD

(d₆-DMSO): 1.28 (9H, s), 1.31-1.38 (2H, m), 1.42-1.51 (4H, m), 1.57-1.65 (2H, m), 1.67-1.77 (4H, m), 1.84-1.93 (2H, m), 1.97-2.08 (1H, m),2.09-2.37 (1H, m), 2.26-2.38 (4H, m), 3.14 (4H, t, J = 5.2 Hz), 3.47(2H, s), 4.76-4.85 (1H, m), 5.54 (1H, t, J = 4.0 Hz), 6.32 (1H, s), 7.05(1H, d, J = 8.5 Hz), 7.16 (1H, dd, J = 2.0, 10.0 Hz), 72.4-7.34 (3H, m),73.4-7.40 (2H, m), 7.41- 7.43 (1H, m), 7.47 (1H, t, J = 2.0 Hz),7.59-7.64 (2H, m), 8.18 (1H, s). (Method 5): Rt 3.68 min, m/z 736, 738[MH⁺]. 19 1-methyl piperazine (3.0 eq.) SeD

(d₆-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.78 )4H, m), 1.84-1.95 (2H, m), 1.97-2.07 (1H, m), 2.10 (3H, s), 2.09-2.18 (1H, m),2.19-2.47 (7H, m), 3.14 (4H, t, J = 5.1 Hz), 3.32 (1H, m, obscured bywater), 3.50 (2H, s), 4.80 (1H, dd, J = 6.4, 8.2 Hz), 5.54 (1H, t, J =4.1 Hz), 6.32 (1H, s), 7.05 (1H, broad d, J = 8.3 Hz), 7.16 (1H, dd, J =2.0, 10.0 Hz), 7.24-7.34 (3H, m), 7.34- 7.40 (2H, m), 7.42 (1H, s),7.46- 7.51 (1H, m), 7.58-7.65 (2H, m), 8.19 (1H, s). (Method 5): Rt 3.66min, m/z 751, 753 [MH⁺]. 20 Dimethylamine (2M in MeOH) TfD

(d₆-DMSO): 1.21 (9H, s), 1.54- 1.60 (2H, m), 1.54-1.72 (4H, m),1.74-1.84 (1H, m), 1.86-1.94 (1H, m), 1.96-2.08 (2H, m), 2.16 (6H, s),2.59 (2H, t, J = 5.6 Hz), 3.09 (4H, t, J = 5.3 Hz), 4.05 (2H, t, J = 5.7Hz), 4.77 (1H, td, J = 8.4, 5.5 Hz), 5.50 (1H, t, J = 4.5 Hz), 6.28 (1H,s), 6.95 (1H, d, J = 8.5 Hz), 7.05-7.12 (3H, m), 7.19-7.27 (3H, m), 7.33(1H, dd, J = 7.6, 1.1 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.56 (1H, d, J =9.9 Hz), 7.58 (1H, d, J = 1.7 Hz), 7.89 (1H, s), 8.12 (1.4H, s). (Method5): Rt 3.59 mins, m/z 726 [MH⁺]. 21 Morpholilne (3.0 eq.) UcC

(d₆-DMSO): 0.56 (3H, d, J = 6.2 Hz), 0.59 (3H, d, J = 6.2 Hz), 1.24 (9H,s), 1.36-1.56 (3H, m), 1.64- 1.70 (2H, m), 1.73-1.80 (1H, m), 1.80-1.92(2H, m), 1.97-2.10 (2H, m), 2.34 (4H, t, J = 4.3 Hz), 3.08- 3.22 (2H,m), 3.48 (2H, s), 3.51 (4H, t, J = 4.5 Hz), 4.77 (1H, td, J = 8.4, 6.1Hz), 5.48 (1H, t, J = 4.1 Hz), 6.29 (1H, s), 7.05 (1H, d, J = 8.6 Hz),7.13 (1H, d, J = 9.5 Hz), 7.17 (1H, dd, J = 9.9, 2.2 Hz), 7.19-7.33 (6H,m), 7.62 (1H, d, J = 10.0 Hz), 7.84 (1H, d, J = 1.7 Hz), 8.13 (1H, s),8.15 (0.25 H, br s). (Method 5): Rt 3.86 mins, m/z 750 [MH⁺]. 221-Methyl-piperazine (3.0 eq.) UcC

(d₆-DMSO): 0.55 (3H, d, J = 6.1 Hz), 0.59 (3H, d, J = 6.1 Hz), 1.23 (9H,s), 1.35-1.56 (3H, m), 1.63- 1.69 (2H, m), 1.73-1.80 (1H, m), 1.80-1.92(2H, m), 1.95-2.10 (2H, m), 2.08 (3H, s), 2.22-2.42 (10H, br m),3.10-3.22 (2H, m), 3.47 (3H, s), 4.77 (1H, td, J = 8.6, 5.9 Hz), 5.48(1H, t, J = 4.2 Hz), 6.29 (1H, s), 7.05 (1H, d, J = 8.7 Hz), 7.10 (1H,d, J = 9.6 Hz), 7.17 (1H, dd, J = 9.8, 2.2 Hz), 7.19-7.28 (5H, m),7.29-7.32 (1H, m), 7.62 (1H, d, J = 9.7 Hz), 7.84 (1H, d, J = 1.8 Hz),8.14 (2.2H, s). (Method 5): Rt 3.89 mins, m/z 763 [MH⁺]. 23Dimethylamine (2M in MeOH) WeC

(d₆-DMSO): 0.56 (3H, d, J = 6.3 Hz), 0.59 (3H, d, J = 6.3 Hz), 1.23 (9H,s), 1.35-1.57 (3H, m), 1.64- 1.70 (2H, m), 1.72-1.80 (1H, m), 1.81-1.93(2H, m), 1.95-2.10 (2H, m), 2.15 (6H, s), 2.58 (2H, t, J = 5.7 Hz),3.10-3.20 (2H, m), 4.06 (2H, t, J = 5.7 Hz), 4.78 (1H, td, J = 8.8, 5.9Hz), 5.49 (1H, t, J = 4.0 Hz), 6.29 (1H, s), 6.83 (1H, dt, J = 10.9, 2.2Hz), 6.90-6.95 (2H, m), 7.11 (1H, d, J = 8.7 Hz), 7.17 (1H, dd, J = 9.8,2.2 Hz), 7.20-7.33 (4H, m), 7.62 (1H, d, J = 9.8 Hz), 7.84 (1H, d, J =1.9 Hz), 8.12 (1.3H, s), 8.14 (1H, s). (Method 5): Rt 3.86 mins, m/z 738[MH⁺]. 24 Morpholine (3.0 eq.) UcB

(d₆-DMSO): 0.86 (3H, d, J = 6.3 Hz), 1.24 (9H, s), 1.42-1.52 (2H, m),1.58-1.68 (2H, m), 1.72-1.92 (4H, m), 1.96-2.05 (1H, m), 2.05- 2.14 (1H,m), 2.34 (4H, t, J = 4.0 Hz), 2.86 (1H, ddd, J = 12.6, 9.0, 3.9 Hz),3.12 (1H, dt, J = 11.7, 3.9 Hz), 1H, obscured by solvent, 3.48 (2H, s),3.52 (4H, t, J = 4.4 Hz), 4.77 (1H, td, J = 8.3, 6.9 Hz), 5.47 (1H, t, J= 4.1 Hz), 6.29 (1H, s), 7.04 (1H, d, J = 8.6 Hz), 7.13 (1H, d, J = 9.2Hz), 7.15 (1H, dd, J = 9.8, 2.1 Hz), 7.20-7.31 (5H, m), 7.31- 7.34 (1H,d, J = 7.2 Hz), 7.60 (1H, d, J = 9.9 Hz), 7.65 (1H, d, J = 1.9 Hz), 8.12(1H, s), 8.19 (0.15H, br s). (Method 5): Rt 3.69 mins, m/z 736 [MH⁺]. 25N—Me-piperazine (3.0 eq.) UcB

(d₆-DMSO): 0.86 (3H, d, J = 6.4 Hz), 1.24 (9H, s), 1.43-1.52 (2H, m),1.58-1.68 (2H, m), 1.70-1.92 (4H, m), 1.96-2.04 (1H, m), 2.08 (3H, s),2.08-2.13 (1H, m), 2.20- 2.40 (10H, br m), 2.86 (1H, ddd, J = 12.6, 9.3,4.0 Hz), 3.12 (1H, dt, J = 11.6, 4.1 Hz), 3.24-3.31 (1H, m), 3.48 (2H,s), 4.77 (1H, td, J = 8.3, 6.0 Hz), 5.47 (1H, t, J = 4.0 Hz), 6.29 (1H,s), 7.06 (1H, d, J = 8.6 Hz), 7.10 (1H, d, J = 9.3 Hz), 7.15 (1H, dd, J= 9.9, 2.1 Hz), 7.21-7.29 (5H, m), 7.31-7.35 (1H, m), 7.60 (1H, d, J =9.7 Hz), 7.65 (1H, d, J = 1.9 Hz), 8.15 (1.2H, s), 8.16 (1H, s). (Method5): Rt 3.73 mins, m/z 749 [MH⁺]. 26 Dimethylamine (2M in MeOH) WeB

(d₆-DMSO): 0.86 (3H, d, J = 6.3 Hz), 1.23 (9H, s), 1.42-1.51 (2H, m),1.58-1.68 (2H, m), 1.70-1.82 (2H, m), 1.82-1.92 (2H, m), 1.95- 2.04 (1H,m), 2.08-2.14 (1H, m), 2.14 (6H, s), 2.58 (2H, t, J = 5.7 Hz), 2.86 (1H,ddd, J = 12.6, 9.3, 4.1 Hz), 3.12 (1H, dt, J = 11.9, 4.1 Hz), 3.24-3.31(1H, m), 4.06 (2H, t, J = 5.7 Hz), 4.77 (1H, td, J = 8.2, 6.3 Hz), 5.47(1H, t, J = 4.0 Hz), 6.29 (1H, s), 6.83 (1H, dt, J = 10.8, 2.2 Hz),6.90-6.95 (2H, m), 7.13 (1H, d, J = 8.6 Hz), 7.16 (1H, dd, J = 9.9, 2.1Hz), 7.20-7.26 (2H, m), 7.26-7.30 (1H, m), 7.30-7.34 (1H, m), 7.60 (1H,d, J = 9.8 Hz), 7.65 (1H, d, J = 1.9 Hz), 8.14 (1.2H, s), 8.18 (1H, s).(Method 5): Rt 3.71 mins, m/z 724 [MH⁺]. 27 Dimethylamine (2M in MeOH)XdB

(d₆-DMSO): 0.86 (3H, d, J = 6.3 Hz), 1.24 (9H, s), 1.42-1.52 (2H, m),1.58-1.68 (2H, m), 1.70-1.82 (2H, m), 1.82-1.90 (2H, m), 1.94- 2.04 (1H,m), 2.06-2.14 (1H, m), 2.14 (6H, s), 2.58-2.62 (2H, m), 2.86 (1H, ddd, J= 12.8, 9.0, 4.1 Hz), 3.12 (1H, dt, J = 12.0, 4.3 Hz), 3.24-3.30 (1H,m), 4.18 (2H, t, J = 5.7 Hz), 4.75 (1H, td, J = 8.5, 5.8 Hz), 5.47 (1H,t, J = 4.1 Hz), 6.33 (1H, s), 7.14 (1H, dd, J = 9.7, 2.1 Hz), 7.17-7.21(2H, m), 7.22- 7.30 (3H, m), 7.33 (1H, dd, J = 7.3, 1.6 Hz), 7.39 (1H,d, J = 1.8 Hz), 7.60 (1H, dd, J = 9.8, 0.7 Hz), 7.65 (1H, d, J = 1.9Hz), 7.79 (1H, d, J = 16.3 Hz), 8.23 (0.4H, s), 8.38 (1H, s). (Method5): Rt 3.72 mins, m/z 731 [MH⁺]. 28 [1,4]-Oxazepane (3.0 eq.)Intermediate 53d

(d₆-DMSO): 1.28 (9H, s), 1.57- 1.65 (2H, m), 1.67-1.77 (6H, m),1.79-1.97 (2H, m), 1.98-2.17 (2H, m), 2.69-2.75 (4H, m), 2.87- 2.92 (2H,m), 3.14 (4H, t, J = 5.2 Hz, obscured by water), 3.52-3.56 (2H, m,obscured by water), 3.60 (2H, t, J = 6.0 Hz, obscured by water), 4.17(2H, t, J = 5.7 Hz), 4.76-4.85 (1H, m), 5.55 (1H, t, J = 4.1 Hz), 6.34(1H, s), 7.06-7.12 (2H, m), 7.15 (1H, dd, J = 10.1, 2.0 Hz), 7.22-7.36(4H, m), 7.39 (1H, dd, J = 7.4, 1.7 Hz), 7.54 (1H, d, J = 8.6 Hz),7.59-7.64 (2H, m), 8.14- 8.19 (2H, m). (Method 5): Rt 3.60 mins, m/z782.4 [MH⁺]. 29 8-Oxa-3-aza- bicyclo[3.2.1]octane (3.0 eq.) Intermediate53d

(d₆-DMSO): 1.28 (9H, s), 1.57-1.78 (8H, m), 1.79-1.96 (4H, m), 1.98-2.17 (2H, m), 2.62 (2H, t, J = 6.0 Hz), 3.10-3.17 (6H, m, obscured bywater), ~3.33 (2H, completely obscured by water), 3.45-3.50 (2H, m,obscured by water), 4.17 (2H, t, J = 5.8 Hz), 4.77-4.85 (1H, m), 5.55(1H, t, J = 4.2 Hz), 6.34 (1H, s), 7.07-7.17 (3H, m), 7.22-7.41 (5H, m),7.54 (1H, d, J = 8.5 Hz), 7.60- 7.64 (2H, m), 8.18 (1H, s), 8.21 (0.6H,s). (Method 5): Rt 3.63 mins, m/z 794.6 [MH⁺]. 30 Dimethylamine (2Msolution in THF) ReB

(d₆-DMSO): 0.91 (3H, d, J = 6.2 Hz), 1.28 (9H, s), 1.46-1.56 (2H, m),1.62-1.73 (2H, m), 1.74-1.98 (4H, m), 1.99-2.17 (2H, m), 2.21 (6H, s),2.50-2.56 (2H, m, obscured by solvent), 2.85-2.95 (3H, m), 3.12-3.20(1H, m, obscured by water), 3.27-3.36 (1H, m, obscured by water),4.76-4.85 (1H, m), 5.51 (1H, t, J = 4.2 Hz), 6.33 (1H, s), 7.08 (1H, d,J = 8.5 Hz), 7.19 (1H, dd, J = 10.0, 2.0 Hz), 7.23-7.42 (5H, m),7.52-7.56 (2H, m), 7.64 (1H, d, J = 9.8 Hz), 7.69 (1H, d, J = 1.9 Hz),8.16 (1H, s), 8.17 (1.8H, s). (Method 5): Rt 3.70 mins, m/z 724.5 [MH⁺].31 Dimethylamine (2M solution in THF) ReC

(d₆-DMSO): 0.60 (3H, d, J = 6.1 Hz), 0.63 (3H, d, J = 6.1 Hz), 1.28 (9H,s), 1.38-1.61 (3H, m), 1.66- 1.75 (2H, m), 1.76-1.98 (3H, m), 2.02-2.12(2H, m), 2.18 (6H, s), 2.87 (2H, br, t, J = 7.8 Hz), 3.12- 3.24 (4H, m,obscured by water), 4.77-4.85 (1H, m), 5.52 (1H, t, J = 4.2 Hz), 6.33(1H, s), 7.07 (1H, d, J = 8.7 Hz), 7.18-7.41 (6H, m), 7.51- 7.55 (2H,m), 7.67 (1H, d, J = 10.1 Hz), 7.88 (1H, d, J = 2.4 Hz), 8.14 (1H, s),8.18 (0.9H, s). (Method 5): Rt 3.87 mins, m/z 738.4 [MH⁺]. 32 Morpholine(3.0 eq.) ReC

(d₆-DMSO): 0.60 (3H, d, J = 6.1 Hz), 0.64 (3H, d, J = 6.1 Hz), 1.28 (9H,s), 1.38-1.61 (3H, m), 1.66- 1.75 (2H, m), 1.76-1.97 (3H, m), 2.01-2.13(2H, m), 2.38-2.44 (4H, m), 2.50-2.56 (2H, m, obscured by solvent),2.86-2.93 (2H, m), 3.12- 3.23 (2H, m, obscured by water), 3.54 (4H, t, J= 4.5 Hz), 4.76-4.85 (1H, m), 5.52 (1H, t, J = 4.2 Hz), 6.33 (1H, s),7.07 (1H, d, J = 8.4 Hz), 7.18-7.42 (6H, m), 7.51-7.57 (2H, m), 7.66(1H, d, J = 10.0 Hz), 7.88 (1H, d, J = 2.1 Hz), 8.15 (1H, s), 8.22(0.4H, s). (Method 5): Rt 3.88 mins, m/z 780.4 [MH⁺]. 33 1-Methylpiperazine (3.0 eq.) ReC

(d₆-DMSO): 0.60 (3H, d, J = 6.1 Hz), 6.3 (3H, d, J = 6.1 Hz), 1.28 (9H,s), 1.37-1.62 (3H, m), 1.67- 1.75 (2H, m), 1.77-1.98 (3H, m), 2.02-2.11(2H, m), 2.12 (3H, s), 2.20-2.36 (4H, m), 2.37-2.48 (4H, m), 2.84-2.91(2H, m), 3.12-3.23 (4H, m, obscured by water), 4.77- 4.85 (1H, m), 5.53(1H, t, J = 4.3 Hz), 6.32 (1H, s), 7.07 (1H, d, J = 8.6 Hz), 7.17-7.41(6H, m), 7.51- 7.56 (2H, m), 7.66 (1H, d, J = 9.9 Hz), 7.88 (1H, d, J =2.1 Hz), 8.14 (1H, s), 8.18 (1H, s). (Method 5): Rt 3.84 mins, m/z 793.4[MH⁺]. 34 4-Methoxy-piperidine (3.0 eq.) YeB

(d₆-DMSO): 0.91 (3H, d, J = 6.2 Hz), 1.27 (9H, s), 1.32-1.43 (2H, m),1.44-1.56 (2H, m), 1.60-1.72 (2H, m), 1.72-1.97 (6H, m), 1.99- 2.17 (4H,m), 2.50-2.56 (2H, m, obscured by solvent), 2.68-2.76 (2H, m), 2.76-2.83(2H, m), 2.86- 2.95 (1H, m), 3.07-3.17 (2H, m), 3.18 (3H, s), 3.27-3.36(1H, m, obscured by water), 4.76-4.86 (1H, m), 5.52 (1H, t, J = 4.1 Hz),6.31 (1H, s), 7.06 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.8, 2.1 Hz),7.24- 7.40 (6H, m), 7.47 (1H, dd, J = 6.9, 2.7 Hz), 7.64 (1H, d, J = 9.8Hz), 7.69 (1H, d, J = 1.6 Hz), 8.08 (1H, s), 8.17 (1.5H, s). (Method 5):Rt 3.70 mins, m/z 778.6 [MH⁺]. 35 Azetidine (3.0 eq.) YeB

(d₆-DMSO): 0.91 (3H, d, J = 6.1 Hz), 1.27 (9H, s), 1.46-1.56 (2H, m),1.61-1.73 (2H, m), 1.75-1.87 (2H, m), 1.88-1.97 (4H, m), 1.99- 2.17 (2H,m), 2.63 (4H, s), 2.86- 2.94 (1H, m), 3.15 (4H, t, J = 7.0 Hz),3.12-3.19 (1H, m), 3.27-3.35 (1H, m, obscured by water), 4.77- 4.85 (1H,m), 5.51 (1H, t, J = 4.2 Hz), 6.32 (1H, s), 7.10 (1H, d, J = 8.5 Hz),7.19 (1H, dd, J = 9.9, 2.2 Hz), 7.23-7.40 (6H, m), 7.43 (1H, dd, J =6.8, 2.8 Hz), 7.64 (1H, d, J = 10.1 Hz), 7.69 (1H, d, J = 1.7 Hz), 8.13(1H, s), 8.19 (1.5H, s). (Method 5): Rt 3.67 mins, m/z 720.5 [MH⁺]. 36Azetidin-3-yl- dimethyl-amine (3.0 eq.) YeB

(d₆-DMSO): 0.91 (3H, d, J = 6.0 Hz), 1.27 (9H, s), 1.45-1.56 (2H, m),1.61-1.72 (2H, m), 1.74-1.94 (4H, m), 1.96 (6H, s), 1.98-2.18 (2H, m),2.64 (4H, s), 2.68-2.80 (3H, m), 2.86-2.95 (1H, m), 3.12- 3.20 (1H, m),3.27-3.35 (1H, m), 3.38 (2H, t, J = 5.4 Hz), 4.77-4.86 (1H, m), 5.52(1H, t, J = 4.2 Hz), 6.31 (1H, s), 7.07 (1H, d, J = 8.7 Hz), 7.19 (1H,dd, J = 10.0, 2.1 Hz), 7.23-7.39 (6H, m), 7.43 (1H, dd, J = 6.8, 2.6Hz), 7.64 (1H, d, J = 9.6 Hz), 7.69 (1H, d, J = 2.0 Hz), 8.09 (1H, s),8.17 (1.7H, s). (Method 5): Rt 3.34 mins, m/z 763.6 [MH⁺]. 37Dimethylamine (2M solution in THF) YeB

(d₆-DMSO): 0.91 (3H, d, J = 6.1 Hz), 1.28 (9H, s), 1.45-1.56 (2H, m),1.61-1.72 (2H, m), 1.74-1.98 (4H, m), 1.99-2.16 (2H, m), 2.18 (6H, s),2.51-2.55 (2H, m, obscured by solvent), 2.79 (2H, t, J = 5.7 Hz),2.86-2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water), 3.27-3.36 (1H,m, obscured by water), 4.77- 4.86 (1H, m), 5.51 (1H, t, J = 4.3 Hz),6.32 (1H, s), 7.08 (1H, d, J = 8.5 Hz), 7.19 (1H, dd, J = 9.9, 2.1 Hz),7.24-7.39 (6H, m), 7.46 (1H, dd, J = 6.7, 2.5 Hz), 7.64 (1H, d, J = 10.1Hz), 7.69 (1H, d, J = 1.6 Hz), 8.10 (1H, s), 8.18 (1.3H, s). (Method 5):Rt: 3.60 min, m/z 708.5 [MH⁺]. 38 Dimethylamine (2M solution in THF)Intermediate 53dE

(d₆-DMSO): 1.28 (9H, s), 1.81-2.26 (9H, m), 2.13 (3H, s), 2.19 (6H, s),2.32-2.39 (1H, m), 2.63 (2H, t, J = 5.7 Hz), 3.11-3.16 (1H, m), 3.99(1H, t, J = 8.2 Hz), 4.15 (2H, t, J = 5.7 Hz), 4.81 (1H, td, J = 8.6,5.6 Hz), 5.39 (1H, t, J = 4.3 Hz), 6.34 (1H, s), 7.08 (1H, t, J = 2.4Hz), 7.11 (1H, t, J = 2.4 Hz), 7.24-7.41 (6H, m), 7.54 (1H, d, J = 8.5Hz), 7.76 (1H, d, J = 9.9 Hz), 8.14 (1H, s), 8.25 (1H, d, J = 2.1 Hz).(Method 5): Rt 2.80 min, m/z 726.5 [MH⁺]. 39 Morpholine (3.0 eq.)Intermediate 77c

(d₆-DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.43-1.57 (2H, m),1.63-1.73 (2H, m), 1.75-1.96 (4H, m), 2.01-2.17 (2H, m), 2.45 (4H, t, J= 4.5 Hz), 2.65-2.75 (2H, m), 2.91 (1H, ddd, J = 12.2, 9.3, 4.2 Hz),3.16 (1H, dt, J = 12.2, 4.2 Hz), 3.27-3.33 (1H, m), 3.51 (4H, t, J = 4.6Hz), 4.20 (2H, t, J = 5.7 Hz), 4.81 (1H, td, J = 8.6, 5.5 Hz), 5.52 (1H,t, J = 4.3 Hz), 6.34 (1H, s), 7.07 (1H, d, J = 8.7 Hz), 7.10 (1H, dd, J= 8.6, 2.4 Hz), 7.18 (1H, dd, J = 9.8, 2.2 Hz), 7.23-7.38 (5H, m), 7.54(1H, d, J = 8.5 Hz), 7.61 (1H, dd, J = 9.8, 0.8 Hz), 7.70 (1H, d, J =2.1 Hz), 8.13 (1H, s). (Method 5): Rt 3.72 min, m/z 782.6 [MH⁺]. 40Pyrrolidine (3.0 eq.) MeB

(d₆-DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.43-1.56 (2H, m),1.63-1.72 (6H, m), 1.76-1.96 (4H, m), 2.00-2.16 (2H, m), 2.53 (4H, d, J= 7.9 Hz), 2.90 (1H, ddd, J = 12.3, 8.9, 4.1 Hz), 3.16 (1H, dt, J =12.3, 4.0 Hz), 3.29-3.34 (1H, m), 3.71 (2H, s), 4.80 (1H, td, J = 8.5,5.5 Hz), 5.51 (1H, t, J = 4.3 Hz), 6.32 (1H, s), 6.99 (1H, d, J = 8.5Hz), 7.19 (1H, dd, J = 9.8, 2.2 Hz), 7.23-7.32 (3H, m), 7.36 (1H, td, J= 7.5, 1.6 Hz), 7.42 (1H, dd, J = 8.5, 2.6 Hz), 7.54 (1H, d, J = 8.5Hz), 7.60 (1H, d, J = 2.6 Hz), 7.64 (1H, dd, J = 9.9, 0.8 Hz), 7.68 (1H,dd, J = 2.1, 0.9 Hz), 8.14 (1H, s), 8.16 (1.4H, s). (Method 5): Rt 3.70min, m/z 736.5 [MH⁺]. 41 Morpholine (3.0 eq.) MeB

(d₆-DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.47-1.55 (2H, m),1.63-1.71 (2H, m), 1.75-1.96 (4H, m), 2.00-2.16 (2H, m), 2.44 (4H, t, J= 4.2 Hz), 2.92-2.90 (1H, ddd, J = 12.3, 9.2, 4.1 Hz), 3.16 (1H, dt, J =12.1, 4.1 Hz), 3.29-3.34 (1H, m), 3.55 (4H, t, J = 4.5 Hz), 3.59 (2H,s), 4.80 (1H, td, J = 8.6, 5.6 Hz), 5.51 (1H, t, J = 4.3 Hz), 6.33 (1H,s), 7.00 (1H, d, J = 8.5 Hz), 7.19 (1H, dd, J = 9.8, 2.1 Hz), 7.22-7.32(3H, m), 7.35 (1H, td, J = 7.4, 1.6 Hz), 7.44 (1H, dd, J = 8.6, 2.6 Hz),7.56 (1H, d, J = 8.5 Hz), 7.62-7.65 (2H, m), 7.69 (1H, dd, J = 2.1, 0.9Hz), 8.17 (1H, s), 8.17 (1H, s). (Method 5): Rt 3.74 min, m/z 752.5[MH⁺]. 42 N-methyl piperazine (3.0 eq.) MeB

(d₆-DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.45-1.56 (2H, m),1.62-1.71 (2H, m), 1.76-1.97 (4H, m), 2.00-2.16 (2H, m), 2.12 (3H, s),2.32 (4H, br s), 2.46 (4H, br s), 2.90 (1H, ddd, J = 12.2, 9.2, 4.2 Hz),3.16 (1H, dt, J = 12.2, 4.2 Hz), 3.29-3.34 (1H, m), 3.58 (2H, s), 4.81(1H, td, J = 8.5, 5.6 Hz), 5.51 (1H, t, J = 4.3 Hz), 6.33 (1H, s), 6.99(1H, d, J = 8.5 Hz), 7.19 (1H, dd, J = 9.8, 2.2 Hz), 7.25 (1H, d, J =7.6 Hz), 7.28 (1H, dd, J = 7.3, 1.7 Hz), 7.31 (1H, dd, J = 7.4, 1.8 Hz),7.36 (1H, td, J = 7.5, 1.6 Hz), 7.43 (1H, dd, J = 8.6, 2.6 Hz), 7.55(1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 2.6 Hz), 7.64 (1H, dd, J = 9.8,0.8 Hz), 7.69 (1H, dd, J = 2.1, 0.9 Hz), 8.16 (1H, s), 8.17 (1.5H, brs). (Method 5): Rt 3.76 min, m/z 765.6 [MH⁺]. 43 Morpholine (3.0 eq.)MeC

(d₆-DMSO): 0.60 (3H, d, J = 6.2 Hz), 0.63 (3H, d, J = 6.2 Hz), 1.28 (9H,s), 1.39-1.60 (3H, m), 1.68- 1.74 (2H, m), 1.77-1.97 (3H, m), 2.02-2.12(2H, m), 2.44 (4H, t, J = 4.2 Hz), 3.13-3.23 (2H, m), 3.55 (4H, t, J =4.5 Hz), 3.59 (2H, s), 4.81 (1H, td, J = 8.6, 5.5 Hz), 5.52 (1H, t, J =4.3 Hz), 6.33 (1H, s), 7.00 (1H, d, J = 8.5 Hz), 7.21 (1H, dd, J = 9.9,2.1 Hz), 7.24-7.35 (4H, m), 7.44 (1H, dd, J = 8.5, 2.6 Hz), 7.56 (1H, d,J = 8.5 Hz), 7.63 (1H, d, J = 2.6 Hz), 7.67 (1H, d, J = 9.8 Hz), 7.88(1H, d, J = 2.1 Hz), 8.17 (2H, s). (Method 5): Rt 3.93 min, m/z 766.6[MH⁺]. 44 N-methyl piperazine (3.0 eq.) MeC

(d₆-DMSO): 0.60 (3H, d, J = 6.2 Hz), 0.63 (3H, d, J = 6.2 Hz), 1.28 (9H,s), 1.25-1.60 (3H, m), 1.68- 1.73 (2H, m), 1.77-1.97 (3H, m), 2.02-2.12(2H, m), 2.12 (3H, s), 2.32 (4H, br s), 2.46 (4H, br s), 3.13-3.23 (2H,m), 3.57 (2H, s), 4.81 (1H, td, J = 8.6, 5.5 Hz), 5.53 (1H, t, J = 4.3Hz), 6.33 (1H, s), 7.01 (1H, d, J = 8.5 Hz), 7.21 (1H, dd, J = 9.8, 2.2Hz), 7.24-7.36 (4H, m), 7.43 (1H, dd, J = 8.5, 2.6 Hz), 7.55 (1H, d, J =8.5 Hz), 7.60 (1H, d, J = 2.6 Hz), 7.67 (1H, d, J = 9.8 Hz), 7.88 (1H,d, J = 2.1 Hz), 8.18 (1.5H, s), 8.19 (1H, s). (Method 5): Rt 3.92 min,m/z 779.6 [MH⁺]. 45 Pyrrolidine (3.0 eq.) ZcB

(d₆-DMSO): 0.90 (3H, d, J = 6.2 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.66(6H, m), 1.74-2.16 (7H, m), 2.47 (m, signal overlapped with solventpeak), 2.90 (1H, m), 3.16 (m, signal overlapped with solvent peak), 3.65(2H, s), 4.80 (1H, m), 5.51 (1H, t, J = 4.2 Hz), 6.31 (1H, s), 7.03 (1H,d, J = 8.6 Hz), 7.19 (1H, dd, J = 10.0, 2.1 Hz), 7.22- 7.39 (5H, m),7.42 (1H, m), 7.50 (1H, dd, J = 6.7, 2.9 Hz), 7.64 (1H, d, J = 10.1 Hz),7.68 (1H, m), 8.11 (1H, s), 8.21 (1H, s). (Method 5): Rt 3.63 mins, m/z720 [MH⁺]. 46 1-Methyl piperazine (3.0 eq.) ZcB

(d₆-DMSO): 0.91 (3H, d, J = 6.6 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.66(2H, m), 1.74-2.15 (6H, m), 2.09 (3H, s), 2.28 (4H, m), 2.42 (4H, m),2.90 (1H, m), 3.16 (m, signal overlapped with solvent peak), 3.54 (s,signal overlapped with solvent peak), 4.81 (1H, m), 5.51 (1H, t, J = 4.4Hz), 6.31 (1H, s), 7.02 (1H, d, J = 8.4 Hz), 7.19 (1H, dd, J = 9.7, 2.2Hz), 7.23-7.39 (5H, m), 7.43 (1H, m), 7.48 (1H, dd, J = 6.7, 2.7 Hz),7.64 (1H, d, J = 9.7 Hz), 7.68 (1H, d, J = 1.8 Hz)), 8.13 (1H, s), 8.21(1H, s). (Method 5): Rt 3.64 mins, m/z 749 [MH⁺]. 47 Morpholine (3.0eq.) ZcB

(d₆-DMSO): 0.91 (3H, d, J = 6.2 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.66(2H, m), 1.74-1.96 (4H, m), 1.99-2.17 (2H, m), 2.40 (4H, m), 2.90 (1H,m), 3.16 (1H, m), 3.50- 3.57 (6H, m), 4.80 (1H, m), 5.51 (1H, t, J = 4.1Hz), 6.31 (1H, s), 7.04 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.7, 2.1Hz), 7.22-7.38 (5H, m), 7.44 (1H, m), 7.51 (1H, dd, J = 6.4, 2.6 Hz),7.64 (1H, d, J = 9.7 Hz), 7.69 (1H, d, J = 1.6 Hz)), 8.14 (1H, s), 8.40(0.2H, s). (Method 5): Rt 3.62 mins, m/z 736 [MH⁺].

Example 481-[5-tert-Butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.1-[5-tert-Butyl-2-(4-chloro-3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 48a)

A solution of[5-tert-butyl-2-(4-chloro-3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporatedherein by reference; 190 mg, 0.32 mmol), Intermediate D (105 mg, 0.289mmol) and DIPEA (0.075 mL, 0.43 mmol) in dioxane (4 mL) was stirred at60° C. for 18 h. The cooled solution was concentrated in vacuo,redissolved in EtOAc (20 mL), then washed with water (10 mL), brine (10mL), dried (Na₂SO₄), filtered and concentrated in vacuo. FCC, using 2%MeOH in EtOAc, gave the title compound (202 mg, 86%). LCMS (Method 3):Rt 5.63 mins, m/z 811 [MH⁺].

b.1-[5-tert-Butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea.(Example 48)

To a solution of Intermediate 48a (198 mg, 0.24 mmol) in THF (4 mL) wasadded TBAF (1M in THF, 0.29 mL, 0.29 mmol) and the red solution wasstirred at RT for 15 min. The solution was concentrated in vacuo,suspended in water (10 mL) and extracted with EtOAc (2×10 mL). Thecombined organics were washed with brine (10 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. FCC, using 4-8% MeOH in DCM, gavethe title compound (124 mg, 78%). LCMS (Method 5): Rt 4.50 min, m/z 655[MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.27 (9H, s), 1.60-1.63 (2H, m),1.70-1.75 (4H, m), 1.84-1.96 (2H, m), 1.99-2.13 (2H, m), 3.14 (4H, t,J=5.2 Hz), 4.82 (1H, m), 5.55 (1H, t, J 4.4), 6.33 (1H, s), 6.94 (1H,dd, J=8.5, 2.4 Hz), 7.08 (1H, d, J=8.5 Hz), 7.12 (1H, d, J=2.4 Hz), 7.16(1H, dd, J=9.8, 2.2 Hz), 7.27-7.39 (4H, m), 7.43 (1H, d, J=8.5 Hz),7.60-7.63 (2H, m), 8.13 (1H, s), 10.59 (1H, br s).

Example 491-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.1-[5-tert-Butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 49a)

A solution of[5-tert-Butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloroethyl ester (WO2011/154734A, which is incorporatedherein by reference; 157 mg, 0.26 mmol), Intermediate D (91.0 mg, 0.25mmol) and DIPEA (0.054 mL, 0.31 mmol) in dioxane (4 mL) was stirred at60° C. for 18 h, and at 100° C. for 1 h. The cooled solution wasconcentrated in vacuo, suspended in water (4 mL) and extracted with DCM(2×4 mL). The combined organics were passed through a hydrophobic fritand concentrated in vacuo. FCC, using 0-4% [2M NH₃ in MeOH] in DCM, gavea solid (153 mg, 75%). LCMS (Method 3): Rt 5.53 min, m/z 811 [MH⁺].

b.1-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea.(Example 49)

A solution of Intermediate 49a (152 mg, 0.19 mmol) and TBAF (1M in THF,0.225 mL, 0.225 mmol) in THF (4 mL) was stirred at RT for 10 min. Thesolution was concentrated in vacuo, suspended in water (5 mL) andextracted with EtOAc (2×5 mL). The combined organics were washed withbrine (5 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. FCC,using 5-15% [2M NH₃ in MeOH] in DCM, gave a solid. Further purificationby HPLC (XBridge C18 column, 25-75% MeCN in H₂O, 0.1% NH₄OH) gave thetitle compound (42.9 mg, 35%). LCMS (Method 5): Rt 4.46 min, m/z 655[MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.26 (9H, s), 1.60-1.66 (2H, m),1.69-1.76 (4H, m), 1.82-1.96 (2H, m), 1.99-2.07 (1H, m), 2.09-2.16 (1H,m), 3.14 (4H, t, J=5.2 Hz), 4.78-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz),6.28 (1H, s), 7.05 (2H, d, J=8.6 Hz), 7.16 (1H, dd, J=2.2, 9.8 Hz),7.29-7.27 (4H, m), 7.38 (1H, d, J=7.6 Hz), 7.43 (1H, d, J=2.5 Hz), 7.61(1H, dd, J=0.7, 11.9 Hz), 7.62 (1H, s), 8.00 (1H, s), 10.46 (1H, br s).

Example 501-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

a.1-[5-tert-Butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 50a)

A mixture of Intermediate E (145 mg, 0.40 mmol) and[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporatedherein by reference, 251 mg, 0.420 mmol) in 1,4-dioxane (4 mL) and DIPEA(110 μL, 0.63 mmol) was stirred at 90° C. for 5.5 h. The cooled mixturewas concentrated in vacuo. The residue was purified by FCC, using 0-12%MeOH in DCM, to give the title compound (288 mg, 89%). LCMS (Method 3):Rt 3.85 min, m/z 811 [MH⁺].

b.1-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Example 50)

A solution of Intermediate 50a (280 mg, 0.345 mmol) and TBAF (1M in THF,0.41 mL, 0.41 mmol) in THF (3 mL) was stirred at RT for 0.5 h. Water wasadded and the mixture extracted with DCM (3×15 mL). The combinedorganics were concentrated in vacuo. The residue was purified by FCC,using 0-14% MeOH in DCM, to give the title compound (154 mg, 68%). LCMS(Method 5): Rt 3.52 min, m/z 655.2 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO):1.26 (9H, s), 1.82-2.26 (11H, m), 2.31-2.39 (1H, m), 3.10-3.16 (1H, m),3.99 (1H, d, J=8.2 Hz), 4.77-4.85 (1H, m), 5.35-5.42 (1H, m), 6.28 (1H,s), 7.03-7.10 (2H, m), 7.22-7.38 (6H, m), 7.43 (1H, d, J=2.5 Hz), 7.75(1H, dd, J=9.9 Hz), 7.99 (1H, s), 8.24 (1H, br d), 10.56 (1H, v br).

Example 511-[5-tert-Butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

The title compound (193 mg, 76%) was prepared starting from IntermediateE (155 mg, 0.427 mmol) and[5-tert-butyl-2-(4-chloro-3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporatedherein by reference, 260 mg, 0.436 mmol), using analogous procedures tothose described in Example 50. LCMS (Method 5): Rt 3.54 min, m/z 655.2[MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.27 (9H, s), 1.82-2.26 (11H, m),2.31-2.39 (1H, m), 3.10-3.17 (1H, m), 3.99 (1H, d, J=8.1 Hz), 4.78-4.86(1H, m), 5.37-5.42 (1H, m), 6.33 (1H, s), 6.89-6.95 (1H, br d),7.07-7.12 (2H, m), 7.24-7.38 (5H, m), 7.42 (1H, d, J=8.4 Hz), 7.75 (1H,dd, J=9.8 Hz), 8.12 (1H, s), 8.25 (1H, br d), 10.64 (1H, v br).

Example 521-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-hydroxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl}-urea

A solution of Intermediate G (153 mg, 0.28 mmol) and[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporatedherein by reference, 167 mg, 0.28 mmol) in 1,4-dioxane (4 mL) and DIPEA(87 μL, 0.50 mmol) was stirred at 95° C. for 4 h. The cooled mixture wasconcentrated in vacuo. The residue was purified by FCC, using 0-7.5%MeOH in DCM, to give1-[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(193 mg). This was dissolved in THF (3 mL) and treated with TBAF (1M inTHF, 0.47 mL, 0.47 mmol). The solution was stirred at RT for 1.75 h,then diluted with water and extracted with DCM (3×20 mL). The combinedorganics were dried and concentrated in vacuo. The residue was purifiedby FCC, using 0-25% [2M NH₃ in MeOH] in DCM, to give the product. Thiswas further purified by HPLC (C18 X-select column, 30-98% MeCN in H₂O,0.1% HCO₂H) to give the title compound (72 mg, 56%). LCMS (Method 5): Rt3.99 min, m/z 685 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.26 (9H, s),1.38-1.52 (2H, m), 1.55-1.66 (11H, m), 1.73-1.96 (4H, m), 1.98-2.17 (2H,m), 2.85-2.97 (2H, m), 3.3-3.5 (4H, m, under water signal), 4.52 (1H, brs), 4.77-4.85 (1H, m), 5.55 (1H, br t, J=4.4 Hz), 6.28 (1H, s), 7.05(1H, s), 7.08 (1H, s), 7.15 (1H, dd, J=2.0, 9.8 Hz), 7.23-7.40 (5H, m),7.44 (1H, d, J=2.5 Hz), 7.61 (1H, d, J=9.9 Hz), 7.64 (1H, br d, J=1.5Hz), 8.02 (1H, br s), 10.55 (1H, br s).

Example 531-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.5-tert-Butyl-2-{4-chloro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate 53a)

To a solution of 5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol(WO2011/154734A1, which is incorporated herein by reference, 340 mg,1.28 mmol), 2-(tetrahydro-pyran-2-yloxy)-ethanol (0.26 mL, 1.92 mmol)and Ph₃P (671 mg, 2.56 mmol) in dry THF (10 mL) was addeddiethylazodicarboxylate (0.41 mL, 2.56 mmol) and the mixture stirred for10 min. Water (4 drops) was added and the mixture concentrated in vacuo.The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, togive the title compound (450 mg, 89%). LCMS (Method 3): Rt 3.73 min, m/z394 [MH⁺].

b.(5-tert-Butyl-2-{4-chloro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 53b)

To a solution of Intermediate 53a (445 mg, 1.13 mmol) in EtOAc (4 mL)and 1N sodium hydroxide solution (2.40 mL, 2.40 mmol) was added2,2,2-trichloroethyl chloroformate (165 μL, 1.20 mmol), and the mixturestirred vigorously at RT for 1.5 h. The aqueous layer was extracted withEtOAc (2×10 mL), and then the combined organics dried and concentratedin vacuo. The residue was purified by FCC, using 0-30% EtOAc incyclohexane, to give the title compound (650 mg, 100%). LCMS (Method 3):Rt 4.90 min, m/z 568, 570, 572 [MH⁺].

c.1-(5-tert-Butyl-2-{4-chloro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 53c)

A solution of Intermediate D (408 mg, 1.12 mmol) and Intermediate 53b(640 mg, 1.12 mmol) in 1,4-dioxane (4 mL) and DIPEA (300 μL, 1.70 mmol)was stirred at 70° C. for 16 h. The mixture was cooled, then water addedand the mixture extracted with DCM (4×10 mL). The combined organics weredried and concentrated in vacuo. The residue was purified by FCC, using0-10% MeOH in DCM, to give the title compound (836 mg, 95%). LCMS(Method 3): Rt 4.27 min, m/z 783 [MH⁺].

d.1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 53)

A solution of Intermediate 53c (830 mg, 1.06 mmol) and pyridiniump-toluenesulphonate (799 mg, 3.18 mmol) in methanol (7 mL) was stirredat 40-45° C. for 18.5 h. The cooled mixture was concentrated in vacuo,diluted with sat. sodium hydrogen carbonate solution and extracted withDCM (3×15 mL). The combined organics were dried and concentrated invacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to givethe product as a solid (613 mg, 83%). An aliquot (50 mg) was furtherpurified by HPLC (XBridge C18 column, 30-90% MeCN in H₂O, 0.1% NH₄OH) togive the title compound (38 mg). LCMS (Method 5): Rt 4.42 min, m/z 699.5[MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m),1.68-1.77 (4H, m), 1.80-1.97 (2H, m), 1.98-2.17 (2H, m), 3.11-3.17 (4H,m), 3.74 (2H, q, J=5.0 Hz), 4.12 (2H, t, J=5.0 Hz), 4.76-4.85 (1H, m),4.90 (1H, t, J=5.1 Hz), 5.54 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.05-7.11(2H, m), 7.16 (1H, dd, J=2.0, 9.9 Hz), 7.21-7.41 (5H, m), 7.54 (1H, d,J=8.5 Hz), 7.59-7.65 (2H, m), 8.14 (1H, br s).

Example 541-[5-tert-Butyl-2-(3-hydroxy-5-methyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a. 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-5-methyl-phenol (Intermediate54a)

5-tert-Butyl-2H-pyrazol-3-ylamine (1.11 g, 8.00 mmol), potassiumcarbonate (2.32 g, 16.8 mmol), copper (I) iodide (0.076 g, 0.40 mmol),and 3-bromo-5-methylphenol (1.80 g, 9.60 mmol) were weighed into a largemicrowave vial. This was then purged with argon thentrans-N,N-dimethylcyclohexane-1,2-diamine (0.25 mL, 1.60 mmol) added. Tothis mixture was then added degassed toluene (8 mL). The mixture wasthen purged with argon again, the vial sealed, and heated for 1 h at140° C. in the microwave, then a further 4 h at 135° C. The mixture wascooled, diluted with ethyl acetate and passed through a pad ofcelite/silica, washing with more ethyl acetate. The dark solution wasconcentrated in vacuo. The residue was purified by FCC, using 0-40% DCMin EtOAc, to give the title compound (966 mg, 49%). ¹H NMR (300 MHz,CDCl₃): 1.32 (9H, s), 2.24 (3H, s), 3.82 (2H, br s), 5.49 (1H, s),6.45-6.52 (1H, m), 6.65-6.71 (1H, m), 6.85-6.91 (1H, m).

b.5-tert-Butyl-2-(3-methyl-5-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-ylamine(Intermediate 54b)

To a solution of Intermediate 54a (430 mg, 1.75 mmol) in DCM (10 mL) andtriethylamine (0.36 mL, 2.63 mmol) was addedtriisopropylsilyltrifluoromethanesulphonate (0.52 mL, 1.93 mmol).Mixture stirred for 1 h at RT, diluted with DCM, washed with sat. sodiumhydrogen carbonate solution then brine, dried, and concentrated invacuo. The residue was purified by FCC, using 0-25% EtOAc incyclohexane, to give impure title compound (740 mg), contaminated withthe ˜25% bis-silyl impurity. ¹H NMR (300 MHz, CDCl₃): inter alia1.03-1.15 (18H, m), 1.18-1.35 (12H, m), 2.32 (3H, s), 3.74 (2H, br s),5.49 (1H, s), 6.60-6.66 (1H, m), 6.85-6.89 (1H, m), 6.95-7.00 (1H, m).

c.[5-tert-Butyl-2-(3-methyl-5-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 54c)

To a solution of Intermediate 54b (0.73 g, assumed 1.70 mmol) in ethylacetate (8 mL) was added 1N sodium hydroxide solution (4.5 mL, 4.50mmol). Stirred for 5 min then 2,2,2-trichloroethyl chloroformate (275μL, 2.00 mmol) was added and the mixture stirred vigorously at RT for3.5 h. Diluted with EtOAc, washed with water and brine, dried, andconcentrated in vacuo. The residue was purified by FCC, using 0-15%EtOAc in cyclohexane, to give the still impure title compound (1.01 g).¹H NMR (300 MHz, CDCl₃): inter alia 1.02-1.15 (18H, m), 1.18-1.38 (12H,m), 2.34 (3H, s), 4.82 (2H, s), 6.43 (1H, s), 6.69-6.77 (2H, m),6.84-6.96 (2H, m).

d.1-[5-tert-Butyl-2-(3-methyl-5-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 54d)

A solution of Intermediate D (170 mg, 0.468 mmol) and Intermediate 54c(386 mg, 0.47 mmol) in 1,4-dioxane (4 mL) and DIPEA (122 μL, 0.70 mmol)was stirred at 95° C. for 3 h. The mixture was cooled and concentratedin vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, togive the title compound (306 mg, 83%). LCMS (Method 3): Rt 5.57 min, m/z791.2 [MH⁺].

e.1-[5-tert-Butyl-2-(3-hydroxy-5-methyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 54)

To a solution of Intermediate 54d (300 mg, 0.38 mmol) in THF (4 mL) wasadded a solution of tetrabutylammonium fluoride in THF (1M, 0.49 mL,0.49 mmol). Stirred at RT for 0.5 h, then diluted with water andextracted with DCM (5×20 mL). The combined organics were dried andconcentrated in vacuo. The residue was purified by FCC, using 0-10% MeOHin DCM, to give the impure product as a solid (210 mg). This was furtherpurified by HPLC (XBridge C18 column, 40-85% MeCN in H₂O, 0.1% NH₄OH) togive the title compound (73 mg, 30%). LCMS (Method 5): Rt 4.44 min, m/z635.3 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.26 (9H, s), 1.57-1.65 (2H, m),1.68-1.77 (4H, m), 1.81-1.98 (2H, m), 1.99-2.18 (2H, m), 2.27 (3H, s),3.10-3.18 (4H, m), 4.79-4.88 (1H, m), 5.55 (1H, t, J=4.3 Hz), 6.31 (1H,s), 6.59-6.64 (1H, m), 6.67-6.71 (1H, m), 6.71-6.74 (1H, m), 7.09-7.19(2H, m), 7.25-7.41 (4H, m), 7.58-7.65 (2H, m), 8.06 (1H, br s), 9.65(1H, br s).

Examples 55, 56, and 57 a.4-Iodo-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester(Intermediate 55a)

To a solution of 4-Iodo-methyl salicylate (2.00 g, 7.20 mmol) andtriphenylphosphine (3.77 g, 14.4 mmol) in THF (20 mL), under Argonatmosphere, was added 2-(tetrahydro-pyran-2-yloxy)-ethanol (1.54 mL,10.8 mmol) followed by dropwise addition of DEAD (2.84 mL, 14.4 mmol).The reaction was stirred at RT overnight. The reaction mixture waspartitioned between water (50 mL) and EtOAc (50 mL). The organic phasewas washed with brine and dried over Na₂SO₄ and evaporated under reducedpressure. The residue was purified by FCC, eluting with 0-20% EtOAc inDCM, to give the title compound as a colourless oil (2.64 g, 90%). ¹HNMR (300 MHz, CDCl₃): 1.48-1.67 (4H, m), 1.68-1.90 (2H, m), 3.5-3.59(1H, m), 3.75-3.94 (5H, m), 3.96-4.13 (1H, m), 4.14-4.27 (2H, m), 4.75(1H, t), 7.33 (1H, dd, J=8.23, 1.45 Hz), 7.40 (1H, d, J=1.5 Hz), 7.47(1H, d, J=8.3 Hz).

b.4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoicacid methyl ester (Intermediate 55b)

A solution of Intermediate 55a (2.64 g, 6.50 mmol),3-tert-butyl-1H-pyrazole-5-amine (997 mg, 7.1 mmol) andtrans-N,N′-dimethylcyclohexane-diamine (185 mg, 0.33 mmol) was formed intoluene (25 mL). Potassium carbonate (1.9 g, 13.7 mmol) was added andthe mixture degassed by bubbling nitrogen through it. Copper(I) iodide(64.0 mg, 1.30 mmol) was added and the mixture was refluxed at 110° C.for 24 h. The solvent was evaporated under reduce pressure and theresidue was partitioned between EtOAc/Water and extracted with EtOAc.The combined organics were dried over Na₂SO₄, filtered and evaporated.Purification by FCC eluting with a gradient of 0-50% EtOAc incyclohexane gave the title compound (1.72 g, 64%). LCMS (Method 3): Rt3.69 min, m/z 418 [MH⁺].

c.{4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-methanol(Intermediate 55c)

A solution of Intermediate 55b (1.72 g, 4.12 mmol) in THF (30 mL) wastreated with LiAlH₄ (2M in THF, 2.5 mL, 4.94 mmol) [CARE: gasevolution]. The reaction mixture was left to stir at RT for 5 h. Thereaction was quenched slowly with water and the product was extractedwith EtOAc. The organic phase was separated, washed with brine, driedover Na₂SO₄, and evaporated under reduced pressure to give the titlecompound (1.57 g, 95%). LCMS (Method 3): Rt 2.80 min, m/z 390 [MH⁺].

d.5-tert-Butyl-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-4-triisopropylsilanyloxy-methyl-phenyl}-2H-pyrazol-3-ylamine(Intermediate 55d)

A solution of Intermediate 55c (1.57 g, 4.03 mmol) and imidazole (581mg, 8.06 mmol) in THF (80 mL) was treated with chlorotriisopropylsilane(1.37 mL, 6.04 mmol). The reaction mixture was refluxed for 24 h. Thereaction was evaporated under reduced pressure and the residue waspartitioned between water and EtOAc. The organic phase was separated,washed with brine, dried over Na₂SO₄, and evaporated under reducedpressure. The product was purified by FCC, eluting with 0-40% EtOAc incyclohexane, to give the title compound (2.3 g, 95%). LCMS (Method 3):Rt 5.53 min., m/z 546 [MH⁺].

e.5-tert-Butyl-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-4-triisopropylsilanyloxymethyl-phenyl}-2H-pyrazol-3-ylamine(Intermediate 55e)

To a solution of Intermediate 55d (2.30 g, 4.21 mmol) in EtOAc (20 mL)was added NaOH 1N (8 mL, 7.94 mmol) followed by2,2,2-trichloroethylchloroformate (637 L, 4.63 mmol). The reaction wasstirred for 2 h at RT and then partitioned between EtOAc and water. Theaqueous layer was then extracted with EtOAc (3×60 mL). The combinedorganic layers were washed with brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The residue was purified by FCC, using 0-30% EtOAcin cyclohexane, to give the title compound (1.57 g, 40%). ¹H NMR (300MHz, CDCl₃): 1.05-1.13 (18H, m), 1.14-1.26 (3H, m), 1.45-1.67 (4H, m),1.68-1.87 (2H, m), 3.47-3.59 (1H, m), 3.74-3.82 (1H, m), 3.83-3.93 (1H,m), 3.99-4.11 (1H, m), 4.11-4.22 (3H, m), 4.71 (1H, t, J=3.2 Hz), 4.81(2H, s), 4.88 (2H, s), 6.44 (1H, bs), 6.96 (1H, d, J=1.63 Hz), 7.03 (1H,dd, J=7.97, 1.74 Hz), 7.67 (1H, d, J=7.97 Hz).

f.1-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-4-triisopropylsilanyloxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 55eB)

A solution of Intermediate 55e (343 mg, 0.48 mmol), Intermediate B (180mg, 0.48 mmol) and DIPEA (118 μL, 0.71 mmol) in 1,4-dioxane (5 mL) wasstirred at 60° C. overnight. After cooling, the mixture was partitionedbetween EtOAc and water. The aqueous layer was then extracted with EtOAc(3×10 mL). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo to give a gum (505 mg, 95%)that was used without further purification in the next step. TLC[DCM/MeOH (19:1); Rf=0.5]. A solution of the above product (505 mg, 0.50mmol) in MeOH (25 mL) was treated with pyridinium p-toluene sulfonate(400 mg, 1.60 mmol) and the resulting mixture was heated at 45° C.overnight. The volatiles were removed under reduced pressure and theresidue was taken up in DCM (40 mL) and washed with water (10 mL). Theorganic phase was separated using a phase separating cartridge and theorganic layer was evaporated in vacuo. The product was purified by FCC,eluting with 0-10% MeOH in DCM, to give the title compound (260 mg,57%). LCMS (Method 3): Rt 5.21 min, m/z 865,866 [MH⁺].

g. Methanesulfonic acid2-{5-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-2-triisopropylsilanyloxymethyl-phenoxy}-ethylester (Intermediate 55fB)

A mixture of Intermediate 55eB (26.0 mg, 0.30 mmol), methanesulfonylchloride (70.0 μL, 0.90 mmol) and DIPEA (208 μL, 1.20 mmol) in DCM (8mL) was stirred at RT for 1 h. The reaction mixture was partitionedbetween DCM and water. The organic layer was washed with brine,separated through a phase separating cartridge and concentrated in vacuoto afford the title compound (275 mg, 97%). LCMS (Method 3): Rt 5.23min, m/z 943 [MH⁺].

h.1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-4-triisopropylsilanyloxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 55gB)

A mixture of Intermediate 55fB (100 mg, 0.11 mmol) and dimethylamine(2.0M in THF, 0.80 mL, 1.60 mmol) in THF (3 mL) was stirred at 60° C.for 18 h in a sealed vial. The volatiles were concentrated in vacuo andthe residue was used in the next step without further purification (94mg, 100%). LCMS (Method 3): Rt 3.75 min, m/z 893 [MH⁺].

i. General TBAF Deprotection Procedure

A solution of the silyl protected alcohol (e.g Intermediate 55gB, 0.10mmol) in THF (2 mL) was treated with tetrabutyl ammonium fluoride (1M inTHF, 0.50 mmol) and the resulting mixture was heated at 50° C. for 24 h.The volatiles were evaporated under reduced pressure and the residue waspartitioned between saturated solution of NaHCO₃ (10 mL) and DCM (20mL). The product was extracted in DCM and the organic phase wasseparated with a phase separating cartridge and evaporated under reducedpressure. The product was purified by HPLC (Gemini C18, 20-35% MeCN inH₂O, 0.1% HCO₂H, 18 ml/min.) and freeze dried to afford the titlecompound (40-50%).

Table 4 summarises the examples prepared using analogous proceduresdescribed in step (h), using Intermediate 55fB with the appropriateamine, and step (i).

TABLE 4 Ex. Amine No. used Example Structure NMR (400 MHz) δ LCMS 55Dimethyl- amine

(CDCl₃): 0.9 (3H, d, J = 6.59 Hz), 1.27 (9H, s), 1.45-1.56 (2H, m),1.62-1.71 (2H, m), 1.74-1.87 (2H, m), 1.88-2.15 (4H, m), 2.19 (6H, s),2.62 (2H, t, J = 5.5 Hz), 2.85-2.95 (2H, m), 3.11-3.19 (2H, m), 4.09(2H, t, J = 5.6 Hz), 4.53 (2H, s), 4.78-4.86 (1H, m), 5.51 (1H, t, J =3.9), 6.33 (1H, s), 7.04-7.08 (2H, d), 7.09-7.14 (1H, dd, J = 8.0 Hz),7.16-7.20 (1H, dd, J = 2.1, 10.0 Hz), 7.26-7.3 (2H, d, J = 7.1 Hz),7.30-7.33 (1H, dd), 7.35-7.38 (1H, dd), 7.45- 7.49 (1H, d, J = 7.7 Hz),7.61-7.66 (1H, d, J = 9.9 Hz), 7.69 (1H, d, J = 1.7 Hz), 8.11 (1H, s),8.2 (1.46H, s). (Method 5): Rt 3.55 min., m/z 736.5 [MH⁺]. 56 Pyrroli-dine

(CDCl₃): 0.9 (3H, d, J = 6.6 Hz), 1.27 (9H, s), 1.45-1.56 (2H, m),1.58-1.71 (5H, m), 1.73-1.94 (4H, m), 2.0-2.18 (2H, m), 2.75-2.81 (2H,t, J = 6.0 Hz), 2.84-2.96 (2H, m), 3.11-3.19 (6H, m), 4.11 (2H, t, J =5.5 Hz), 4.53 (2H, s), 4.76-4.86 (1H, q), 5.51 (1H, t, J = 3.9 Hz), 6.33(1H, s), 7.03-7.08 (2H, d), 7.09-7.14 (1H, d, J = 8.0 Hz), 7.15- 7.21(1H, dd, J = 2.1, 10.0 Hz), 7.26- 7.3 (2H, d, J = 7.1 Hz), 7.30-7.34(1H, dd), 7.34-7.38 (1H, dd), 7.45-7.50 (1H, d, J = 7.7 Hz), 7.61-7.67(1H, d, J = 9.9 Hz), 7.69 (1H, d, J = 1.7 Hz), 8.10 (1H, s), 8.19(1.26H, s). (Method 5): Rt 3.60 min, m/z 762 [MH⁺]. 57 1- Methyl piper-azine

(CDCl₃): 0.9 (3H, d, J = 6.6 Hz), 1.28 (9H, s), 1.45-1.62 (4H, m),1.62-1.71 (2H, m), 1.76-1.87 (3H, m), 1.89-1.99 (1H, m), 2.0-2.15 (2H,m), 2.19 (3H, s), 2.36-2.46 (3H, bs), 2.7 (2H, t, J = 5.48 Hz),2.85-2.96 (1H, m), 3.12-3.19 (4H, m), 3.39-3.42 (2H, m), 4.11 (2H, t, J= 5.6 Hz), 4.53 (2H, s), 4.78-4.86 (1H, m), 5.51 (1H, t, J = 3.86 Hz),6.33 (1H, s), 7.03-7.13 (3H, dd), 7.15-7.21 (1H, dd, J = 2.1, 10.0 Hz),7.24-7.3 (2H, d, J = 7.1 Hz), 7.30-7.33 (1H, dd), 7.34-7.39 (1H, dd),7.45-7.50 (1H, d, J = 7.7 Hz), 7.61-7.66 (1H, d, J = 9.9 Hz), 7.69 (1H,d, J = 1.7 Hz), 8.09 (1H, s), 8.13 (1H, s). (Method 5): Rt 3.50 min, m/z791 [MH⁺].

Examples 58, 59, and 60 a.1-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-4-triisopropylsilanyloxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 55eC)

A solution of Intermediate 55e (710 mg, 2.17 mmol), Intermediate C (385mg, 2.17 mmol) and DIPEA (250 μL, 3.25 mmol) in 1,4-dioxane (10 mL) wasstirred at 60° C. overnight. After cooling, the mixture was partitionedbetween EtOAc and water. The aqueous layer was then extracted with EtOAc(3×10 mL). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo to give a gum (1.25 g,quantitative) that was used without further purification in the nextstep. TLC [DCM/MeOH (9:1) Rf=0.4]. A solution of the above product (1.25g, 1.30 mmol) in MeOH (30 mL) was treated with pyridiniump-toluenesulfonate (978 mg, 3.90 mmol) and the resulting mixture washeated at 45° C. overnight. The volatiles were removed under reducedpressure and the residue was taken up in DCM (80 mL) and washed withwater (20 mL). The organic phase was separated using a phase separatingcartridge and the organic layer was evaporated in vacuo. The product waspurified by FCC, eluting with 0-10% MeOH in DCM, to give the titlecompound (430 mg, 40%). LCMS (Method 3): Rt 5.41 min, m/z 879,880 [MH⁺].

b Methanesulfonic acid2-{5-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-2-triisopropylsilanyloxymethyl-phenoxy}-ethyl ester (Intermediate 55fC)

A mixture of Intermediate 55eC (430 mg, 0.49 mmol), methanesulfonylchloride (114 μL, 1.47 mmol) and DIPEA (236 μL, 1.96 mmol) in DCM (10mL) was stirred at RT for 1 h. The reaction mixture was partitionedbetween DCM and water. The organic layer was washed with brine,separated through a phase separating cartridge and concentrated in vacuoto afford the title compound (470 mg, quantitative). LCMS (Method 3): Rt5.41 min, m/z 958 [MH⁺].

c.1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-4-triisopropylsilanyloxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 55gC)

A mixture of Intermediate 55fC (157 mg, 0.16 mmol) and dimethylamine(2.0M in THF, 1.23 mL, 2.46 mmol) in THF (3 mL) was stirred at 40° C.for 72 h in a sealed vial. The volatiles were concentrated in vacuo andthe residue was used in the next step without further purification (149mg, 100%). LCMS (Method 3): Rt 3.58 min, m/z 906.7 [MH⁺].

d. General TBAF deprotection procedure

A solution of the silyl protected alcohol (e.g. Intermediate 55gC, 0.10mmol) in THF (2 mL) was treated with tetrabutyl ammonium fluoride (1M inTHF, 0.50 mmol) and the resulting mixture was heated at 50° C. for 24 h.The volatiles were evaporated under reduced pressure and the residue waspartitioned between saturated solution of NaHCO₃ (10 mL) and DCM (20mL). The product was extracted in DCM and the organic phase wasseparated with a phase separating cartridge and evaporated under reducedpressure. The product was purified by HPLC (Gemini C18, 20-35% MeCN inH₂O, 0.1% HCO₂H, 18 ml/min.) and freeze dried to afford the titlecompound (40-50%).

Table 5 summarises the examples prepared, using analogous procedures asdescribed in step (c), using Intermediate 55fC with the appropriateamine, and step (d).

TABLE 5 Ex. No. Amine Example Structure NMR (400 MHz) δ LCMS 58Dimethyl- amine

(CDCl3): 0.61 (6H, dd, J = 10.88, J = 6.78 Hz), 1.27 (9H, s), 1.37-1.58(3H, m), 1.67- 1.74 (3H, m), 1.76-1.89 (2H, m), 1.91-1.98 (1H, m),2.04-2.11 (1H, m), 2.18 (6H, s), 2.61 (2H, t, J = 6.0 Hz), 3.13-3.22(2H, m), 4.10 (2H, t, J = 5.5 Hz), 4.53 (2H, s), 4.79- 4.86 (1H, q),5.52 (1H, t, J = 3.9 Hz), 6.33 (1H, s), 7.04-7.08 (2H, m), 7.10 (1H, d,J = 8.0 Hz), 7.19 (1H, dd, J = 9.5, .233 Hz), 7.23-7.30 (2H, m),7.30-7.36 (2H, m), 7.47 (1H, d, J = 8.67 Hz), 7.65 (1H, s), 7.67 (1H,m), 7.87 (1H, d, J = 1.99 Hz), 8.07 (1H, s), 8.16 (0.1H, s) (Method 5):Rt min., m/z [MH⁺]. 59 Pyrroli- dine

(CDCl3): 0.61 (6H, dd, J = 10.88, J = 6.78 Hz), 1.27 (9H, s), 1.40-1.58(3H, m), 1.60- 1.65 (4H, m), 1.67-1.74 (3H, m), 1.76-1.89 (2H, m),1.91-1.98 (1H, m), 2.0-2.11 (2H, m), 2.79 (2H, t, J = 6.0 Hz), 3.12-3.22(5H, m), 4.11 (2H, t, J = 5.5 Hz), 4.53 (2H, s), 4.79-4.86 (1H, q), 5.52(1H, t, J = 3.9 Hz), 5.75 (1H, s), 6.33 (1H, s), 7.04-7.08 (2H, m), 7.10(1H, d, J = 8.0 Hz), 7.19 (1H, dd, J = 9.5, J = .2.33 Hz), 7.23-7.30(2H, m), 7.30-7.36 (2H, m), 7.47 (1H, d, J = 8.67 Hz), 7.67 (1H, d, J =9.9 Hz), 7.87 (1H, d, J = 1.99 Hz), 8.09 (1H, s), 8.16 (0.4H, s) (Method5): Rt mins, m/z [MH⁺]. 60 1- Methyl piper- azine

(CDCl3): 0.61 (6H, dd, J = 10.88, J = 6.78 Hz), 1.27 (9H, s), 1.38-1.58(3H, m), 1.67- 1.74 (2H, m), 1.76-1.89 (2H, m), 1.91-1.98 (1H, m),2.04-2.07 (2H, m), 2.08 (3H, s), 2.20-2.30 (3H, bs), 2.37-2.47 (3H, bs),2.66 (2H, t, J = 6.0 Hz), 3.12-3.22 (4H, m), 4.11 (2H, t, J = 5.5 Hz),4.53 (2H, s), 4.79-4.86 (1H, q), 5.53 (1H, t, J = 3.9 Hz), 5.75 (1H, s),6.33 (1H, s), 7.04-7.08 (2H, m), 7.10 (1H, d, J = 8.0 Hz), 7.19 (1H, dd,J = 9.5, J = .2.33 Hz), 7.23-7.30 (2H, m), 7.30-7.36 (2H, m), 7.47 (1H,d, J = 8.67 Hz), 7.67 (1H, d, J = 9.9 Hz), 7.88 (1H, d, J = 1.99 Hz),8.09 (1H, s), 8.16 (0.4H, s) (Method 5): Rt mins, m/z [MH⁺].

Example 611-{5-tert-Butyl-2-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt

a. 5-Iodo-2-triisopropylsilanyloxy-benzoic acid methyl ester(Intermediate 61a)

A solution of methyl 5-iodosalicylate (2.00 g, 7.20 mmol) in DMF (20 mL)was treated with imidazole (1.22 g, 18.0 mmol) thenchlorotriisopropylsilane (1.85 mL, 8.60 mmol). The mixture was stirredat RT for 18 h. The mixture was evaporated in vacuo and the residue waspartitioned between EtOAc and water. The aqueous layer was thenextracted with EtOAc (2×). The combined organic layers were washed witha 10% aqueous citric acid solution, 1N aqueous NaOH solution and brine,dried (Na₂SO₄), filtered and evaporated in vacuo. The residue waspurified by FCC, using 0-10% EtOAc in cyclohexane, to give the titlecompound as a colorless oil (2.88 g, 92%). LCMS (Method 3): Rt 5.72 min,m/z 435 [MH⁺].

b. (5-Iodo-2-triisopropylsilanyloxy-phenyl)-methanol (Intermediate 61b)

A solution of Intermediate 61a (2.88 g, 6.60 mmol) in DCM (50 mL) at 0°C. under N₂ was treated dropwise with diisobutyl aluminium hydride (1.0Min THF, 16.6 mL, 16.6 mmol) and the mixture was stirred at RT overnight.The mixture was cooled to 0° C., then treated dropwise with anotherportion of diisobutyl aluminium hydride (1.0M in THF, 8.3 mL, 8.30 mmol)and stirred at RT for 1 h. The mixture was cooled to 0° C. and quenchedby dropwise addition of water to give a gel that was partitioned betweenEtOAc/ether and brine/water/aqueous potassium sodium tartrate solution.The insoluble salts were filtered off and the phases separated. Theaqueous phase was extracted with EtOAc (2×) and the combined organiclayers were washed with a 10% aqueous citric acid solution, saturatedsodium bicarbonate solution and brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The residue was pre-adsorbed onto diatomaceousearth and purified by FCC, using 0-15% EtOAc in cyclohexane, to give thetitle compound as a colorless oil (1.04 g, 39%). LCMS (Method 3): Rt5.29 min, m/z 405 [MH⁺].

c.[5-(5-Amino-3-tert-butyl-pyrazol-1-yl)-2-triisopropylsilanyloxy-phenyl]-methanol(Intermediate 61c)

3-(Tert-butyl)-1H-pyrazol-5-amine (0.32 g, 2.30 mmol) was treated with asolution of Intermediate 61b (1.04 g, 2.60 mmol) in toluene (4 mL) thenpotassium carbonate (0.68 g, 4.90 mmol),(1S,2S)—N,N′-bis-methyl-1,2-cyclohexane-diamine (0.07 g, 0.47 mmol) andcopper (I) iodide (0.022 g, 0.11 mmol) were added. The mixture wasdegassed then heated at 150° C. for 1 h using microwave irradiation.Another portion of copper (I) iodide (0.022 g, 0.11 mmol) was added andthe reaction mixture heated at 150° C. for a further 1 h using microwaveirradiation. The mixture was diluted with EtOAc and water and the phasesseparated. The aqueous layer was then extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand evaporated in vacuo. The organic layer was evaporated in vacuo. Theresidue was purified by FCC, using 0-15% EtOAc in DCM, to give the titlecompound (0.14 g, 15%). LCMS (Method 3): Rt 3.87 min, m/z 418 [MH⁺].

d.[5-tert-Butyl-2-(3-hydroxymethyl-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 61d)

To a solution of Intermediate 61c (0.15 g, 0.36 mmol) in EtOAc (1.8 mL)was added 1N aqueous NaOH solution (0.6 mL, 0.60 mmol) followed by2,2,2-trichloroethylchloroformate (54.0 μL, 0.40 mmol). The reaction wasstirred at RT overnight then treated with another portion of 1N aqueousNaOH solution (0.3 mL, 0.30 mmol) followed by2,2,2-trichloroethylchloroformate (27.0 μL, 0.20 mmol). After stirringfor another 4 h, the mixture was diluted with EtOAc and water. Theaqueous layer was then extracted with EtOAc (2×). The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered and evaporatedin vacuo. The residue was purified by FCC, using 0-25% EtOAc incyclohexane, to give the title compound (176 mg, 84%). LCMS (Method 3):Rt 5.35 min, m/z 592, 594 [MH⁺].

e.1-[5-tert-Butyl-2-(3-hydroxymethyl-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-((1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 61e)

A solution of Intermediate 61d (173 mg, 0.29 mmol), Intermediate B (100mg, 0.27 mmol) and DIPEA (58 μL, 0.33 mmol) in 1,4-dioxane (2.9 mL) wasstirred at 70° C. for 42 h. The mixture was evaporated in vacuo and theresidue was partitioned between DCM and water. The aqueous layer wasthen extracted with DCM (2×). The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was purified by FCC, using 0-5% MeOH in DCM, to give the titlecompound as a cream colored glass (127 mg, 58%). LCMS (Method 3): Rt4.97 min, m/z 821 [MH⁺].

f.1-[5-tert-Butyl-2-(3-chloromethyl-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 61 f)

A solution of Intermediate 61e (124 mg, 0.15 mmol) in DCM (1.5 mL) at 0°C. was treated with DIPEA (79 μL, 0.45 mmol) then methanesulfonylchloride (23 μL, 0.30 mmol) and the mixture was stirred at RT for 1 h.The mixture was cooled to 0° C. and treated with another portion ofDIPEA (40 μL, 0.23 mmol) and methanesulfonyl chloride (12 μL, 0.15 mmol)and stirred at RT for 30 min. The mixture was diluted with DCM and asaturated aqueous sodium bicarbonate solution. The layers were separatedand the aqueous layer was then extracted with DCM (2×). The combinedorganic layers were washed with water, a saturated aqueous sodiumbicarbonate solution and brine, dried (Na₂SO₄), filtered and evaporatedin vacuo. The residue was purified by FCC, using 0-4% MeOH in DCM, togive the title compound (34 mg, 27%). LCMS (Method 3): Rt 5.56 min, m/z839 [MH⁺].

g.1-{5-tert-Butyl-2-[3-(4-methyl-piperazin-1-ylmethyl)-4-triisopropylsilanyloxy-phenyl]-2H-pyrazol-3-yl)}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 61 g)

A solution of Intermediate 61f (31.0 mg, 0.04 mmol) in THF (0.4 mL) wastreated with 1-methyl-piperazine (41 μL, 0.37 mmol) and the mixture washeated to 50° C. for 64 h. The mixture was evaporated in vacuo and theresidue was partitioned between DCM and water. The aqueous layer wasthen extracted with DCM (2×). The combined organic layers were washedwith water (2×), dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was purified by FCC, using 0-5% [2M NH₃ in MeOH] in DCM, to givethe title compound as a colorless glass (18 mg, 55%). LCMS (Method 3):Rt 3.64 min, m/z 903.7 [MH⁺].

h.1-{5-tert-Butyl-2-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt (Example 61)

A solution of Intermediate 61g (18 mg, 0.02 mmol) in THF (0.10 mL) wastreated with tetrabutylammonium fluoride (1M in THF, 0.10 mL, 0.10 mmol)and the mixture was heated to 50° C. for 2 h. The mixture was dilutedwith DCM and a saturated aqueous sodium bicarbonate solution. The layerswere separated and the aqueous layer was then extracted with DCM (2×).The combined organic layers were washed with brine, dried (Na₂SO₄),filtered and evaporated in vacuo. The residue was purified by HPLC(Method 6; 5-95% MeCN in H₂O, 0.1% HCO₂H over 25 mins) to give the titlecompound (5 mg, 33%). LCMS (Method 5): Rt 3.52 min, m/z 747.6 [MH⁺]. ¹HNMR (400 MHz, d₆-DMSO): 0.91 (3H, d, J=6.4 Hz), 1.26 (9H, s), 1.44-1.56(2H, m), 1.61-1.73 (2H, m), 1.74-1.98 (4H, m), 1.99-2.12 (2H, m), 2.13(3H, s), 2.25-2.37 (3H, m), 2.37-2.49 (5H, m, obscured by DMSO),2.86-2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water), 3.20-3.44 (1Hobscured by water), 3.64 (2H, s), 4.77-4.86 (1H, m), 5.51 (1H, t, J=4.4Hz), 6.28 (1H, s), 6.81-6.85 (1H, m), 7.05 (1H, d, J=8.6 Hz), 7.15-7.21(3H, m), 7.24-7.30 (2H, m), 7.30-7.39 (2H, m), 7.63 (1H, d, J=10.2 Hz),7.69 (1H, d, =J 1.7 Hz), 7.95 (1H, s), 8.36 (0.1H, s).

Example 621-[5-tert-Butyl-2-(3-chloro-5-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

a. 3-Bromo-5-chloro-phenol (Intermediate 62a)

A flask containing (1,5-cyclooctadiene)(methoxy)-iridium(I) dimer (84mg, 0.13 mmol), 4,4′-di-tert butyl-2-2′-dipyridyl (69 mg, 0.26 mmol) andbis(pinacolato)diboron (1.29 g, 5.11 mmol) was purged with Ar, thenhexanes (26 mL) and 1-bromo-3-chlorobenzene (1 mL, 8.51 mmol) were addedsequentially. The solution was stirred at RT for 18 h. The reactionmixture was concentrated in vacuo, re-dissolved in acetone (26 mL), thenoxone (5.23 g, 8.51 mmol) in water (26 mL) added [Caution: exothermobserved]. After 10 min, the reaction mixture was diluted with DCM. Thelayers separated, and the aqueous layer extracted with DCM. The combinedorganics were washed with brine, dried and concentrated in vacuo to givethe title compound (1.43 g, 81%). LCMS (Method 3): Rt 3.74 min, m/z 205,207 [M-H+].

b. 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-5-chloro-phenol (Intermediate62b)

A microwave vial containing 3-tert butyl-1h-pyrazol-5-amine (559 mg,4.02 mmol), Intermediate 62a (1.00 g, 4.82 mmol), copper(I) iodide (38mg, 0.20 mmol) and potassium carbonate (1.16 g, 8.44 mmol) wasrepeatedly purged with argon. Trans-N,N′-dimethylcyclohexane-1,2-diamine(126 μL, 0.80 mmol) was added and the mixture was re-purged with argon.Degassed toluene (4 mL) was added and the resulting suspension wasstirred and heated at 110° C. for 24 h. The cooled suspension was passedthrough Celite pad and diluted with water and extracted with EtOAc. Thecombined organics were dried and concentrated in vacuo. The residue waspurified by FCC, using 0-50% EtOAc in cyclohexane, to give the titlecompound (620 mg, 62%). LCMS (Method 3): Rt 3.13 min, m/z 266 [MH⁺].

c.5-tert-Butyl-2-[3-(tert-butyl-dimethyl-silanyloxy)-5-chloro-phenyl]-2H-pyrazol-3-ylamine(Intermediate 62c)

A solution of Intermediate 62b (615 mg, 2.31 mmol) and imidazole (189mg, 2.78 mmol) in DMF (4.5 mL) was added tert-butyl dimethylchlorosilane(384 mg, 2.55 mmol). The solution was stirred for 2 h then addedtert-butyl dimethylchlorosilane (192 mg, 1.28 mmol). After 1.5 h, thesolution was diluted with water and extracted with EtOAc. The combinedorganics were dried and concentrated in vacuo to give the title compound(831 mg, 94%). LCMS (Method 3): Rt 5.21 min, m/z 380 [MH⁺].

d.{5-tert-Butyl-2-[3-(tert-butyl-dimethyl-silanyloxy)-5-chloro-phenyl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 62d)

To a bi-phasic mixture of Intermediate 62c (807 mg, 2.12 mmol) in EtOAc(7.5 mL) and 1N NaOH solution (1.38 ml, 1.38 mmol) at 0° C. was added2,2,2-trichloroethyl chloroformate (0.35 mL, 2.54 mmol) and the mixturestirred for 5 h. The layers were separated and the organic layer waswashed with brine, dried and concentrated in vacuo to give the titlecompound (1.27 g, 99%). LCMS (Method 3): Rt 5.66 min, m/z 553, 555, 557[MH⁺].

e.1-{5-tert-Butyl-2-[3-(tert-butyl-dimethyl-silanyloxy)-5-chloro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 62e)

A solution of Intermediate 62d (193 mg, 0.35 mmol) and Intermediate E(115 mg, 0.32 mmol) and DIPEA (166 μL, 0.94 mmol) in THF (3.5 mL) wasstirred at reflux for 24 h. The cooled reaction mixture was diluted withwater and extracted with DCM. The combined organics were dried andconcentrated in vacuo to give the title compound (265 mg, 99%). LCMS(Method 3): Rt 3.82 min, m/z 769 [MH⁺].

f.1-[5-tert-Butyl-2-(3-chloro-5-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Example 62f)

A solution of Intermediate 62e (265 mg, 0.32 mmol) and TBAF (1M in THF,0.38 mL, 0.38 mmol) in THF (3 mL) was stirred at RT for 1.3 h, thendiluted with water and extracted with DCM. The combined organics weredried and concentrated in vacuo. The residue was purified by FCC, using0-10% [2M NH₃ in MeOH] in DCM, to give the impure product. This residuewas purified further by HPLC (XBridge C18 column, 35-98% MeCN in H₂O,0.1% NH₄OH) to give the product. This residue purified further by HPLC(XBridge C18 column, 20-98% MeCN in H₂O, 0.1% NH₄OH) to give the titlecompound (63 mg, 30%). LCMS (Method 5): Rt 3.61 min, m/z 655 [MH⁺]. ¹HNMR (400 MHz, d₆-DMSO): 1.27 (9H, s), 1.93-2.12 (5H, m), 2.13 (3H, s),2.14-2.25 (3H, m), 2.34-2.37 (1H, m), 3.12-3.15 (1H, m), 3.99 (1H, t,J=8.2 Hz), 4.80-4.83 (1H, m), 5.39 (1H, t, J=4.2 Hz), 6.31 (1H, s), 6.78(1H, s), 6.89 (1H, s), 6.96 (1H, s), 7.15 (1H, d, J=8.6 Hz), 7.29-7.41(5H, m), 7.75 (1H, dd, J=9.9, 0.8 Hz), 8.14 (1H, s), 8.25 (1H, d, J=2.1Hz).

Example 631-[5-tert-Butyl-2-(3-chloro-5-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound (118 mg, 54%) was prepared in an analogous fashionusing the procedures described in Example 62 (steps (e) and (f)) usingIntermediate 62d and Intermediate D. LCMS (Method 5): Rt 4.65 min, m/z655 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.27 (9H, s), 1.60-1.63 (2H, m),1.71-1.75 (4H, m), 1.89-1.95 (2H, m), 2.01-2.05 (1H, m), 2.13-2.17 (1H,m), 3.14 (4H, t, J=5.2 Hz), 4.80-4.83 (1H, m), 5.54 (1H, t, J=4.2 Hz),6.31 (1H, s), 6.80 (1H, t, J=2.0 Hz), 6.93 (1H, t, J=2.0 Hz), 7.01 (1H,t, J=1.8 Hz), 7.14-7.21 (2H, m), 7.31-7.43 (4H, m), 7.61-7.64 (2H, m),8.16 (1H, s).

Example 641-[5-tert-Butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-[1,4]oxazepan-4-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.1-[5-tert-Butyl-2-(4-chloro-3-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-[1,4]oxazepan-4-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 64a)

A solution of Intermediate F (112 mg, 0.29 mmol),5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamicacid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporatedherein by reference in it is entirety, 194 mg, 0.32 mmol) and DIPEA (155μL, 0.89 mmol) in THF (3 mL) was stirred at reflux for 18 h. The cooledreaction mixture was diluted with water and extracted with DCM. Thecombined organics were dried and concentrated in vacuo to give the titlecompound (243 mg, 99%). LCMS (Method 3): Rt 5.24 min, m/z 827 [MH⁺].

b.1-[5-tert-Butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-[1,4]oxazepan-4-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 64)

A solution of Intermediate 64a (243 mg, 0.29 mmol) and TBAF (LM in THF,1.3 mL, 1.33 mmol) in THF (3 mL) was stirred at RT for 1 h, then dilutedwith water and extracted with DCM (3×20 mL). The combined organics weredried and concentrated in vacuo. The residue was purified by FCC, using0-5% [2M NH₃ in MeOH] in DCM, to give the product. This was furtherpurified by HPLC (XBridge C18 column, 25-98% MeCN in H₂O, 0.1% NH₄OH) togive the title compound (58 mg, 29%). LCMS (Method 5): Rt 4.10 min, m/z671 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.27 (9H, s), 1.84-2.13 (6H, m),3.46-3.50 (4H, m), 3.81-3.92 (4H, m), 4.81-4.85 (1H, m), 5.52 (1H, t,J=4.4 Hz), 6.33 (1H, s), 6.94 (1H, dd, J=8.5, 2.4 Hz), 7.08 (1H, d,J=8.4 Hz), 7.12-7.19 (2H, m), 7.31-7.43 (4H, m), 7.43 (1H, d, J=8.5 Hz),7.60-7.62 (2H, m), 8.12 (1H, s).

Example 651-[5-tert-Butyl-2-(4-chloro-3-piperidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

To a solution of Example 82 (530 mg, 0.79 mmol) and Et₃N (328 μL, 2.37mmol) in DCM (7 mL) at 0° C. was added mesyl chloride (95 μL, 0.95mmol), and the mixture stirred for 0.5 h. The solution was washed withwater, dried, and concentrated in vacuo to give methanesulfonic acid5-(3-tert-butyl-5-{3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureido}-pyrazol-1-yl)-2-chloro-benzylester (390 mg). A portion of this (150 mg, 0.20 mmol) was dissolved inTHF (2 mL) and DIPEA (70 μL, 0.40 mmol) then piperidine (60 μL, 0.60mmol) added and the solution stirred and heated at reflux for 35 min.Water was added and the mixture extracted with DCM. The combinedorganics were dried and concentrated in vacuo. The residue was purifiedby HPLC (XBridge C18 column, 30-98% MeCN in H₂O, 0.1% NH₄OH, 20 mingradient, 18 mL/min) to give the title compound (44 mg, 29%). LCMS(Method 5): Rt 3.59 min, m/z 736 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.28(9H, s), 1.33-1.37 (2H, m), 1.44-1.49 (4H, m), 1.60-1.64 (2H, m),1.69-1.76 (4H, m), 1.87-1.93 (2H, m), 2.03-2.09 (2H, m), 2.40 (4H, t,J=4.8 Hz), 3.14 (4H, t, J=5.2 Hz), 3.53 (2H, s), 4.79-4.82 (1H, m), 5.54(1H, t, J=4.4 Hz), 6.33 (1H, s), 6.97 (1H, d, J=8.5 Hz), 7.15 (1H, dd,J=2.0, 10.0 Hz), 7.29-7.35 (3H, m), 7.39-7.43 (2H, m), 7.54 (1H, d,J=8.5 Hz), 7.60-7.63 (3H, m), 8.16 (1H, s).

Example 661-[5-tert-Butyl-2-(4-chloro-3-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound (45 mg, 31%) was prepared in an analogous fashionusing procedure described for Example 65 using pyrrolidine. LCMS (Method5): Rt 3.53 min, m/z 722 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.28 (9H, s),1.60-1.64 (2H, m), 1.67-1.76 (12H, m), 1.81-1.91 (2H, m), 2.02-2.09 (2H,m), 3.14 (4H, t, J=5.2 Hz), 3.71 (2H, s), 4.77-4.81 (1H, m), 5.54 (1H,t, J=4.3 Hz), 6.32 (1H, s), 6.98 (1H, d, J=8.5 Hz), 7.16 (1H, dd, J=2.0,10.0 Hz), 7.33-7.45 (5H, m), 7.57-7.63 (4H, m), 8.13 (1H, s).

Example 671-{5-tert-Butyl-2-[1-(2-dimethylamino-ethyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}ureaformate salt

a. 4-Fluoro-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyridine(Intermediate 67a)

2-(Tetrahydro-2H-pyran-2yl-oxy)ethanol (731 mg, 679 μL, 5.00 mmol) wassuspended in anhydrous THF and NaH (60% dispersion in mineral oil, 240mg, 6.0 mmol) was added portionwise, resulting in evolution of gas andthe reaction stirred at room temp. After 15 min, a solution of2,4-difluoropyridine (690 mg, 6.00 mmol) in anhydrous THF (2 mL) wasslowly added. After stirring for 2 h, the reaction was partitionedbetween H₂O and EtOAc. The organic layer was separated, and the aqueousextracted again with EtOAc. The combined organics were dried over MgSO₄,concentrated in vacuo and subjected to FCC, eluting with 0-30%EtOAc/cyclohexane, to afford the title compound as a colourless oil (633mg, 43%). LCMS (Method 3) Rt 3.57 min, m/z 264.2 [M+Na].

b. {2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-pyridin-4-yl}-hydrazine(Intermediate 67b)

Intermediate 67a (633 mg, 2.62 mmol) was suspended in EtOH (5 mL) andhydrazine hydrate (50-60%, 5 mL) in a microwave vial fitted with astirrer bar and sealed with a crimped septum, and heated to 80° C. for18 h. The reaction was cooled, and partitioned between H₂O and EtOAc.The organic layer was separated, and the aqueous extracted again withEtOAc. The combined organics were dried over MgSO₄, and concentrated invacuo to afford the title compound as a colorless oil (593 mg, 89%).LCMS (Method 3) Rt 0.41 and 1.71 min, m/z 276.2 [M+Na].

c. 2-[4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-pyridin-2-yloxy]-ethanol(Intermediate 67c)

4,4-Dimethyl-3-oxopentanenitrile (293 mg, 2.34 mmol) and Intermediate67b (593 mg, 2.34 mmol) were suspended in MeOH (10 mL) and a few dropsof concentrated HCl added and the reaction heated to reflux for 72 h.The reaction was cooled, concentrated in vacuo and partitioned betweenH₂O and EtOAc. The organic layer was separated, and the aqueousextracted again with EtOAc. The combined organics were dried over MgSO₄and subjected to FCC, eluting with 10-50% EtOAc/cyclohexane to affordthe title compound after crystallisation (139 mg, 21%). LCMS (Method 3)Rt 2.77 min, m/z 277.3 [MH⁺].

d.{5-tert-Butyl-2-[2-(2-hydroxy-ethoxy)-pyridin-4-yl]-2H-pyrazol-3-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 67d)

To a stirred solution of Intermediate 67c (139 mg, 0.50 mmol) in EtOAc(5 mL) and 1M NaOH solution (1.26 mL, 1.26 mmol) was added2,2,2-trichloroethyl chloroformate (117 mg, 76 μL, 0.55 mmol) and thereaction was stirred at RT. After 1 h, a further 1.1 eq of2,2,2-trichloroethyl chloroformate was added, stirred for an additional1 h, then a further 2.2 eq. of 2,2,2-trichloroethyl chloroformate added.After stirring for an additional 2 h, the reaction was partitionedbetween H₂O and EtOAc. The organic layer was separated, and the aqueouslayer extracted with EtOAc. The combined organics were dried over MgSO₄,concentrated in vacuo and subjected to FCC, eluting with 0-50%EtOAc/cyclohexane, and triturated with Et₂O to afford the title compound(74 mg, 33%). LCMS (Method 3) Rt 3.93 min, 451.1, 453 [MH⁺].

e.1-{5-tert-Butyl-2-[2-(2-hydroxy-ethoxy)-pyridin-4-yl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 67e)

Intermediate 67d (74 mg, 0.16 mmol) and Intermediate B (62 mg, 0.16mmol) were suspended in 1,4-dioxane (5 mL) and DIPEA (32 mg, 42 μL, 0.25mmol) added and the reaction heated to 60° C. for 18 h. The reaction wascooled, concentrated in vacuo and subjected to FCC, eluting with 0-5% 2MNH₃ in MeOH/DCM, to afford the title compound (92 mg, 83%). LCMS (Method3) Rt 3.51 min, 680.4 [MH⁺].

f.1-{5-tert-Butyl-2-[1-(2-dimethylamino-ethyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}ureaformate salt (Example 67)

Intermediate 67e (86 mg, 0.13 mmol) and DIPEA (49 mg, 65 μL) weresuspended in DCM (5 mL) and methanesulfonyl chloride (19 mg, 13 μL, 0.16mmol) was added, and the reaction was stirred at room temp. After 30min, H₂O (5 mL) and DCM (5 mL) was added, stirred, and passed through aphase separator cartridge and the organics concentrated in vacuo. Theresulting residue was then suspended in dimethylamine solution (2M inTHF, 2.5 mL) in a microwave vial, sealed with a crimped septum andstirred at 60° C. The reaction was then cooled, concentrated in vacuo,subjected to FCC, eluting with 0-7% 2M NH₃ in MeOH/DCM, then purifiedfurther by HPLC (Gemini C18, 10-98% MeCN in H₂O, 0.1% HCO₂H, 20 mingradient, 18 mL/min) and the combined fractions freeze dried to affordthe title compound (22 mg, 24%). LCMS (Method 5): Rt 3.55 min, m/z 707.4[MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 0.91 (3H, d, J=6.2 Hz), 1.27 (9H, s),1.46-1.54 (2H, m), 1.61-1.73 (2H, m), 1.75-1.87 (2H, m), 1.89-1.97 (2H,m), 1.99-2.10 (1H, m), 2.17 (6H, s), 2.15-2.22 (2H, m), 2.87-2.95 (1H,m), 3.13-3.20 (1H, dt, J=12.0, 4.5 Hz), 3.32 (2H, m, obscured by water),3.98 (2H, t, J=6.2 Hz), 4.83 (1H, q, J=7.9 Hz), 5.53 (1H, t, J=4.1 Hz),6.37 (1H, s), 6.54-6.56 (1H, m), 6.57-6.61 (1H, dd, J=7.4, 2.4 Hz),7.18-7.23 (1H, dd, J=2.3, 9.9 Hz), 7.24-7.32 (2H, m), 7.35-7.40 (3H, m),7.64 (1H, dd, J=0.8, 9.8 Hz), 7.70-7.72 (1H, m), 7.73 (1H, d, J=7.5 Hz),8.22 (0.25H, s), 8.35 (1H, s).

Example 681-{5-tert-Butyl-2-[4-chloro-3-(piperidin-4-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

To a solution of Intermediate VeD (910 mg, 1.03 mmol) in THF (10 mL) wasadded dropwise tetrabutylammonium fluoride solution (1M in THF, 1.55 mL,1.55 mmol) and the reaction stirred at RT. After stirring for 2.5 h, thereaction was refluxed for another 2 h, then cooled and partitionedbetween H₂O and DCM, and passed through a phase separator cartridge. Theorganics were concentrated in vacuo, and subjected to FCC, eluting with0-20% 2 M NH₃ in MeOH. The crude product (55 mg) obtained after FCC waspurified further by HPLC (XBridge C18 column, 30-98% MeCN in H₂O, 0.1%NH₄OH, 20 min gradient, 18 mL/min) to afford the title compound (32 mg,58%). LCMS (Method 5): Rt 3.61 min, m/z 738, 740 [MH⁺]. ¹H NMR (400 MHz,d₆-DMSO): 1.28 (9H, s), 1.45-1.56 (2H, s), 1.57-1.66 (2H, m), 1.67-1.78(4H, m), 1.81-1.96 (4H, m), 1.97-2.18 (2H, m), 2.53 (2H, m, obscured bysolvent), 2.85-2.95 (2H, m), 3.14 (4H, t, J=5.3 Hz), 4.45 (1H, septet,J=4.2 Hz), 4.76-4.85 (1H, m), 5.55 (1H, t, J=4.3 Hz), 6.33 (1H, s),7.02-7.10 (2H, m), 7.15 (1H, dd, J=2.2, 9.9 Hz), 7.22-7.35 (4H, m),7.36-7.41 (1H, m), 7.54 (1H, d, J=8.6 Hz), 7.58-7.64 (2H, m), 8.14 (1H,s).

Example 691-{5-tert-Butyl-2-[4-chloro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

To a stirred solution of Example 68 (605 mg, 0.82 mmol) in DCM (8 mL)was added formaldehyde solution (37 wt % in H₂O, 610 μL, 8.19 mmol),followed by acetic acid (47 μL, 0.82 mmol), and then sodiumtriacetoxyborohydride (347 mg, 1.64 mmol) and the reaction stirred at RTunder a N₂ atmosphere. After 3 h, the reaction was partitioned betweenH₂O and DCM, and passed through a phase separator cartridge. Theorganics were concentrated in vacuo and subjected to FCC, eluting with0-7.5% 2M NH₃ in MeOH/DCM, and the product purified further by HPLC(XBridge C18 column, 45-85% MeCN in H₂O, 0.1% NH₄OH, 20 min gradient, 18mL/min) to afford the title compound (331 mg, 54%). LCMS (Method 5): Rt3.61 min, m/z 752, 754 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.27 (9H, s),1.58-1.65 (2H, m), 1.65-1.77 (6H, m), 1.80-1.97 (4H, m), 2.11 (3H, s),2.12-2.23 (4H, m), 3.14 (4H, t, J=5.1 Hz), 4.45-4.55 (1H, m), 4.76-4.83(1H, m), 5.55 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.04 (1H, broad d, J=8.4Hz), 7.08 (1H, dd, J=2.3, 8.6 Hz), 7.15 (1H, dd, J=2.2, 9.7 Hz),7.22-7.36 (4H, m), 7.36-7.41 (1H, m), 7.52-7.56 (1H, m), 7.59-7.65 (2H,m), 8.13 (1H, s).

Example 701-{5-tert-Butyl-2-[4-chloro-3-((R)-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared in an analogous fashion to theprocedures described for Example 68, starting from(S)-1-boc-3-hydroxypiperidine. LCMS (Method 5): Rt 3.62 min, m/z 738,740 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.28 (9H, s), 1.33-1.44 (1H, m),1.49-1.68 (4H, m), 1.69-1.78- (4H, m), 1.80-1.96 (2H, m), 1.97-2.08 (2H,m), 2.08-2.17 (1H, m), 2.47 (1H, m, obscured by solvent), 2.55 (1H, m,obscured by solvent), 2.71 (1H, dt, J=4.4, 12.4 Hz), 3.03-3.11 (1H, m),3.14 (4H, t, J=5.2 Hz), 4.33 (1H, septet, J=4.0 Hz), 4.76-4.84 (1H, m),5.54 (1H, t, J=4.1 Hz), 6.33 (1H, s), 7.05 (1H, broad d, J=8.8 Hz), 7.08(1H, dd, J=2.3, 8.4 Hz), 7.15 (1H, dd, J=2.2, 9.7 Hz), 7.23-7.36 (4H,m), 7.36-7.40 (1H, m), 7.54 (1H, d, J=8.8 Hz), 7.59-7.64 (2H, m), 8.14(1H, s), no NH signal observed.

Example 711-{5-tert-Butyl-2-[4-chloro-3-((S)-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared in an analogous fashion to theprocedures described for Example 68, starting from(R)-1-boc-3-hydroxypiperidine. LCMS (Method 5): Rt 3.63 min, m/z 738,740 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.28 (9H, s), 1.33-1.44 (1H, m),1.49-1.68 (4H, m), 1.69-1.78-(4H, m), 1.80-1.96 (2H, m), 1.97-2.08 (2H,m), 2.08-2.17 (1H, m), 2.47 (1H, m, obscured by solvent), 2.55 (1H, m,obscured by solvent), 2.71 (1H, dt, J=4.4, 12.4 Hz), 3.03-3.11 (1H, m),3.14 (4H, t, J=5.2 Hz), 4.33 (1H, septet, J=4.0 Hz), 4.76-4.84 (1H, m),5.54 (1H, t, J=4.1 Hz), 6.33 (1H, s), 7.05 (1H, broad d, J=8.8 Hz), 7.08(1H, dd, J=2.3, 8.4 Hz), 7.15 (1H, dd, J=2.2, 9.7 Hz), 7.23-7.36 (4H,m), 7.36-7.40 (1H, m), 7.54 (1H, d, J=8.8 Hz), 7.59-7.64 (2H, m), 8.14(1H, s), no NH signal observed.

Example 721-{5-tert-Butyl-2-[4-chloro-3-((R)-1-methyl-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

The title compound was prepared in an analogous fashion to theprocedures described for Example 69 starting from Example 70. LCMS(Method 5): Rt 3.64 min, m/z 752, 754 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO):1.28 (9H, s), 1.32-1.56 (2H, m), 1.57-1.65 (2H, m), 1.66-1.77 (5H, m),1.80-2.08 (5H, m), 2.08-2.16 (2H, m), 2.14 (3H, s), 2.78-2.87 (1H, m),3.14 (4H, t, J=5.4 Hz), 4.46 (1H, septet, J=4.2 Hz), 4.77-4.85 (1H, m),5.54 (1H, t, J=4.2 Hz), 6.34 (1H, s), 7.05 (1H, broad d, J=8.6 Hz), 7.10(1H, dd, J=2.2, 8.4 Hz), 7.15 (1H, dd, J=2.1, 10.0 Hz), 7.22-7.35 (4H,m), 7.36-7.40 (1H, m), 7.52-7.56 (1H, m), 7.59-7.64 (2H, m), 8.15 (1H,s).

Example 731-{5-tert-Butyl-2-[4-chloro-3-((S)-1-methyl-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrah.ydro-naphthalen-1-yl]-urea

The title compound was prepared in an analogous fashion to theprocedures described for Example 69 starting from Example 71. LCMS(Method 5): Rt 3.59 min, m/z 752, 754 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO):1.28 (9H, s), 1.32-1.56 (2H, m), 1.57-1.65 (2H, m), 1.66-1.77 (5H, m),1.80-2.08 (5H, m), 2.08-2.16 (2H, m), 2.14 (3H, s), 2.78-2.87 (1H, m),3.14 (4H, t, J=5.4 Hz), 4.46 (1H, septet, J=4.2 Hz), 4.77-4.85 (1H, m),5.54 (1H, t, J=4.2 Hz), 6.34 (1H, s), 7.05 (1H, broad d, J=8.6 Hz), 7.10(1H, dd, J=2.2, 8.4 Hz), 7.15 (1H, dd, J=2.1, 10.0 Hz), 7.22-7.35 (4H,m), 7.36-7.40 (1H, m), 7.52-7.56 (1H, m), 7.59-7.64 (2H, m), 8.15 (1H,s).

Example 741-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-3′-hydroxymethyl-1′H-[1,4′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt

a. 1H-Pyrazole-3-carboxylic acid ethyl ester (Intermediate 74a)

A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) wastreated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol)maintaining the temperature between 20-30° C. with ice bath cooling. Themixture was stirred at RT for 4 h then treated cautiously with water(250 mL) with cooling in an ice bath. The organics were evaporated invacuo and the resulting precipitate was collected by filtration, washedwith water and dried at RT in vacuo to give the title compound (13.5 g,94%). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH⁺].

b. 4-Iodo-1H-pyrazole-3-carboxylic acid ethyl ester (Intermediate 74b)

A suspension of Intermediate 74a (5.00 g, 35.7 mmol) in acetonitrile (90mL) was treated with iodine (9.10 g, 35.7 mmol) then ceric ammoniumnitrate (19.6 g, 35.7 mmol) and the mixture was stirred at RT overnight.Another portion of iodine (2.28 g, 9.0 mmol) was added and the mixturewas stirred for a further 24 h then treated with ice-cold aqueous sodiumhydrogensulphite solution (5%, 100 mL). The mixture was filtered throughCelite rinsing with EtOAc and water. The phases were separated and theaqueous phase was extracted with EtOAc (2×). The combined organic layerswere washed with water and brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The resulting solid was triturated withether/cyclohexane, filtered off, washed with cyclohexane and dried at50° C. in vacuo to give the title compound (3.70 g, 39%). LCMS (Method3): Rt 2.88 min, m/z 267 [MH⁺](weak).

c.4-Iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole-3-carboxylicacid ethyl ester (Intermediate 74c)

A suspension of Intermediate 74b (2.72 g, 10.2 mmol) in acetonitrile (27mL) was treated with caesium carbonate (5.0 g, 15.3 mmol) then2-(2-bromoethoxy)tetrahydro-2H-pyran (1.70 mL, 11.2 mmol) and themixture was stirred at 60° C. for 3.5 h. The mixture was evaporated invacuo and the residue was partitioned between EtOAc and water. Theaqueous layer was then extracted with EtOAc (2×). The combined organiclayers were washed with saturated aqueous sodium bicarbonate solutionand brine, dried (Na₂SO₄), filtered and evaporated in vacuo. The residuewas purified by FCC, using 0-50% EtOAc in cyclohexane, isolating thelower running spot to give the title compound as a colourless glass(1.57 g, 39%). LCMS (Method 3): Rt 3.67 min, m/z 417 [M+Na⁺].

d.{4-Iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-methanol(Intermediate 74d)

A solution of Intermediate 74c (1.22 g, 3.09 mmol) in dry THF (12 mL)was treated with lithium borohydride (0.10 g, 4.64 mmol) and the mixturewas stirred at 60° C. for 5 h then stood at RT overnight. The mixturewas stirred at 60° C. for a further 5 h then cautiously quenched withwater and diluted with EtOAc and water. The phases were separated andthe aqueous layer was extracted with EtOAc (2×). The combined organiclayers were washed with saturated aqueous sodium bicarbonate solutionand brine, dried (Na₂SO₄), filtered and evaporated in vacuo. The residuewas purified by FCC, using 0-100% EtOAc in cyclohexane, to give thetitle compound as a colorless oil (0.68 g, 62%). LCMS (Method 3): Rt2.89 min, m/z 375 [M+Na⁺].

e.{5-Amino-3-tert-butyl-1′-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1′H-[1,4′]bipyrazolyl-3′-yl}-methanol(Intermediate 74e)

A solution of Intermediate 74d (0.51 g, 1.45 mmol) in xylene (2.4 mL)was treated with 3-(tert-butyl)-1H-pyrazol-5-amine (0.18 g, 1.32 mmol)then potassium carbonate (0.38 g, 2.76 mmol),trans-N,N′-Dimethyl-1,2-cyclohexanediamine (0.037 g, 0.26 mmol) andcopper (I) iodide (0.013 g, 0.066 mmol) were added. The mixture wasdegassed then heated at 150° C. for 4 h using microwave irradiation.Another portion of copper (I) iodide (0.006 g, 0.03 mmol) was added andthe reaction mixture heated at 150° C. for a further 2 h using microwaveirradiation. The mixture was diluted with water (1 mL), conc. aqueousammonium hydroxide (1 mL) and EtOAc (1 mL) and the phases separated. Theaqueous layer was then extracted with EtOAc (2×). The combined organiclayers were washed with water and brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The residue was purified by FCC, using 0-5% MeOH inDCM to give the title compound as a dark green gum (0.30 g, 63%). LCMS(Method 3): Rt 2.46 min, m/z 364 [MH⁺].

f.3-tert-Butyl-1′-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-3′-triisopropylsilanyloxymethyl-1′H-[1,4′]bipyrazolyl-5-ylamine(Intermediate 74f)

A solution of Intermediate 74e (0.39 g, 1.10 mmol) in DMF (3.9 mL) wastreated with imidazole (0.18 g, 2.7 mmol) then chlorotriisopropylsilane(0.28 mL, 1.3 mmol) and the mixture was stirred at RT for 22 h. Themixture was evaporated in vacuo and the residue was partitioned betweenEtOAc and water. The aqueous layer was then extracted with EtOAc (2×).The combined organic layers were washed with saturated aqueous sodiumbicarbonate solution and brine, dried (Na₂SO₄), filtered and evaporatedin vacuo. The residue was purified by FCC, using 0-4% MeOH in DCM, togive the title compound (0.44 g, 79%). LCMS (Method 3): Rt 4.20 min, m/z520 [MH⁺].

g.{3-tert-Butyl-1′-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-3′-triisopropylsilanyloxymethyl-1′H-[1,4′]bipyrazolyl-5-yl}-carbamicacid 2,2,2-trichloro-ethyl ester (Intermediate 74g)

To a solution of Intermediate 74f (0.44 g, 0.85 mmol) in EtOAc (5 mL)was added 1N aqueous NaOH solution (1.7 mL, 1.7 mmol) followed by2,2,2-trichloroethylchloroformate (0.13 mL, 0.93 mmol). The reaction wasstirred at RT for 4 h then treated with another portion of2,2,2-trichloroethylchloroformate (35 μL, 0.25 mmol) and stirred overthe weekend. The reaction was treated with another portion of2,2,2-trichloroethylchloroformate (35 μL, 0.25 mmol) and stirred for 1 hthen diluted with EtOAc and water and the layers were separated. Theaqueous layer was then extracted with EtOAc (2×). The combined organiclayers were washed with saturated aqueous sodium bicarbonate solution,and brine, dried (Na₂SO₄), filtered and evaporated in vacuo. The residuewas purified by FCC, using 0-4% MeOH in DCM, to give the title compound(0.47 g, 80%). ¹H NMR (300 MHz, CDCl₃): 0.96 (18H, d, J=6.8 Hz),1.01-1.17 (3H, m), 1.25 (9H, s), 1.38-1.51 (4H, m), 1.54-1.75 (2H, m),3.36-3.45 (1H, m), 3.58-3.68 (1H, m), 3.68-3.77 (1H, m), 3.97-4.07 (1H,m), 4.24 (2H, t, J=4.7 Hz), 4.51 (1H, t, J=3.2 Hz), 4.59 (2H, s),4.69-4.73 (2H, m), 6.26 (1H, s), 7.63 (1H, s), 7.74 (1H, s).

h.1-{3-tert-Butyl-1′-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-3-triisopropylsilanyloxymethyl-1′H-[1,4′]bipyrazolyl-5-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 74h)

Intermediate B (0.23 g, 0.61 mmol) was treated with a solution ofIntermediate 74g (0.47 g, 0.68 mmol) in 1,4-dioxane (3.4 mL) then DIPEA(0.13 mL, 0.74 mmol) was added. The mixture was stirred at 70° C.overnight. The mixture was evaporated in vacuo and the residue waspartitioned between DCM and water. The aqueous layer was then extractedwith DCM (2×). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The residue was purified byFCC, using 0-7% MeOH in DCM, to give the title compound (0.34 g, 60%).LCMS (Method 3): Rt 5.48 min, m/z 923.7 [MH⁺].

i.1-[3-tert-Butyl-1′-(2-hydroxy-ethyl)-3′-triisopropylsilanyloxymethyl-1′H-[1,4′]bipyrazolyl-5-yl]-3-{((1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 74i)

A solution of Intermediate 74h (0.34 g, 0.37 mmol) in MeOH (3.7 mL) wastreated with pyridinium p-toluenesulfonate (0.28 g, 1.1 mmol) and themixture was stirred at 45° C. for 24 h. The mixture was evaporated invacuo and the residue was partitioned between DCM and a saturatedaqueous sodium bicarbonate solution. The aqueous layer was thenextracted with DCM (2×). The combined organic layers were washed withwater, a saturated aqueous sodium bicarbonate solution and brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The residue was purified byFCC, using 0-8% MeOH in DCM, to give the title compound as a goldenglass (142 mg, 46%). LCMS (Method 3): Rt 4.81 min, m/z 839.6 [MH⁺].

j. Methanesulfonic acid2-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-3′-triisopropylsilanyloxymethyl-[1,4′]bipyrazol-1′-yl]-ethylester (Intermediate 74j)

A solution of Intermediate 74i (134 mg, 0.16 mmol) in DCM (1.6 mL) wastreated with DIPEA (83 μL, 0.48 mmol) then cooled to 0° C.Methanesulfonyl chloride was added and the mixture was stirred at 0° C.for 5 min then at RT for 1 h. The mixture was diluted with DCM and asaturated aqueous sodium bicarbonate solution and the phases wereseparated. The aqueous layer was then extracted with DCM (2×). Thecombined organic layers were washed with a saturated aqueous sodiumbicarbonate solution and brine, dried (Na₂SO₄), filtered and evaporatedin vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM, togive the title compound (107 mg, 73%). LCMS (Method 3): Rt 5.06 min, m/z917.4 [MH⁺].

k.1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-3′-triisopropylsilanyloxymethyl-1′H-[1,4′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 74k)

A solution of Intermediate 74j (104 mg, 0.11 mmol) in THF (0.5 mL) wastreated with dimethylamine (2M in THF, 0.57 mL, 1.1 mmol) and themixture was stirred at RT over the weekend. The mixture was evaporatedin vacuo and the residue was partitioned between DCM and water. Theaqueous layer was then extracted with DCM (2×). The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered and evaporatedin vacuo. The residue was purified by FCC, using 0-7% [2M NH₃ in MeOH]in DCM, to give the title compound (79 mg, 81%). LCMS (Method 3): Rt3.46 min, m/z 866.6 [MH⁺].

l.1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-3′-hydroxymethyl-1′H-[1,4′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt (Example 74)

A solution of Intermediate 74k (76 mg, 0.088 mmol) in THF (0.44 mL) wastreated with tetrabutylammonium fluoride (1M in THF, 0.44 mL, 0.44 mmol)and the mixture was heated to 50° C. for 5 h. The mixture was evaporatedin vacuo and the residue was partitioned between DCM and a saturatedaqueous sodium bicarbonate solution. The layers were separated and theaqueous layer was then extracted with DCM (2×). The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered and evaporatedin vacuo. The residue was purified by FCC, using 0-9% [2M NH₃ in MeOH]in DCM. Further purification by HPLC in 3 portions (Method 6, 30-60%MeCN in H₂O, 0.1% HCO₂H over 25 min) gave a colourless glass that wastriturated with ether. The solid was collected by filtration, washedwith ether and dried at 50° C. in vacuo to give the title compound (20mg, 32%). LCMS (Method 5): Rt 3.47 min, m/z 710.5 [MH⁺]. ¹H NMR (400MHz, d₆-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.25 (9H, s), 1.44-1.57 (2H, m),1.61-1.74 (2H, m), 1.74-1.92 (3H, m), 1.92-2.02 (1H, m), 2.01-2.16 (2H,m), 2.18 (6H, s), 2.68 (2H, t, J=6.8 Hz), 2.87-2.95 (1H, m), 3.16 (1H,dt, J=12.0, 4.1 Hz, partially obscured by water), 3.27-3.36 (11, m,obscured by water), 4.16 (2H, t, J=7.0 Hz), 4.31 (2H, s), 4.80-4.88 (1H,m), 4.92-5.11 (0.3H, br s), 5.53 (1H, t, J=4.3 Hz), 6.30 (1H, s),7.14-7.22 (2H, m), 7.25-7.40 (41H, m), 7.64 (1H, d, J=10.0 Hz), 7.70(1H, d, J=1.6 Hz), 8.00 (1H, s), 8.07 (1H, s), 8.19 (1H, s).

Example 751-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

a.5-tert-Butyl-2-{4-chloro-3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-2H-pyrazol-3-ylamine(Intermediate 75a)

To a solution of 5-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol(WO2011/154734A1, which is incorporated herein by reference in it isentirety; 500 mg, 1.88 mmol), and Ph₃P (986 mg, 3.76 mmol) in dry THF(10 mL) was added 3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (Can. J.Chem. Vol. 73, 1195, pp 1682, which is incorporated herein by referencein it is entirety; 452 mg, 2.82 mmol). The resulting mixture was cooledto 0° C. using an ice bath and diethylazodicarboxylate (0.69 mL, 3.76mmol) was added to the chilled mixture which was allowed to warm up toRT. The volatiles were removed under reduced pressure. The residue waspurified by FCC, using 0-50% EtOAc in cyclohexane, to give the titlecompound (739 mg, 96%). LCMS (Method 1): Rt 3.63 min, m/z 408 [MH⁺].

b.(5-tert-Butyl-2-{4-chloro-3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-2H-pyrazol-3-yl)-carbamicacid-2,2,2-trichloro-ethyl ester (Intermediate 75b)

To a solution of Intermediate 75a (739 mg, 1.811 mmol) in EtOAc (9 mL)and 1N sodium hydroxide solution (4.5 mL, 4.53 mmol) was added2,2,2-trichloroethyl chloroformate (341 μL, 2.54 mmol), and the mixturestirred vigorously at RT for 1 h. The aqueous layer was extracted withEtOAc (2×20 mL), and then the combined organics dried and concentratedin vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, togive the title compound (743 mg, 70%). LCMS (Method 4): Rt 4.69 min, m/z582, 584, 586 [MH⁺].

c.1-(5-tert-Butyl-2-{4-chloro-3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Intermediate 75c)

A solution of Intermediate D (153 mg, 0.421 mmol) and Intermediate 75b(265 mg, 0.454 mmol) in DMF (5 mL) and DIPEA (147 μL, 0.84 mmol) wasstirred at 100° C. for 5 h. The mixture was cooled, then water added andthe mixture extracted with EtOAc (50 mL). The combined organics weredried and concentrated in vacuo. The residue was purified by FCC, using0-10% MeOH in DCM, to give the title compound (836 mg, 95%). LCMS(Method 4): Rt 4.04 min, m/z 797 [MH⁺].

d.1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 75)

A solution of Intermediate 75c (247 mg, 0.31 mmol) and pyridiniump-toluenesulphonate (233 mg, 0.93 mmol) in methanol (14 mL) was stirredat 40-45° C. for 18.5 h. The cooled mixture was concentrated in vacuo,diluted with sat. sodium hydrogen carbonate solution and extracted withDCM (3×15 mL). The combined organics were dried and concentrated invacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to givethe product (199.7 mg, 99%). Part of this (50 mg) was further purifiedby HPLC (XBridge C18 column, 30-90% MeCN in H₂O, 0.1% NH₄OH) to give thetitle compound (35 mg). LCMS (Method 5): Rt 4.53 min, m/z 713.4 [MH⁺].¹H NMR (400 MHz, d₆-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77(4H, m), 1.80-1.94 (4H, m), 1.97-2.17 (2H, m), 3.07-3.17 (4H, m),3.48-3.64 (2H, q, J=6.2 Hz), 4.09-4-20 (2H, t, J=6.52 Hz), 4.48-4.58(1H, t, J=5.7), 4.76-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.34 (1H, s),7.05-7.11 (2H, m), 7.16 (1H, dd, J=2.0, 9.9 Hz), 7.21-7.41 (5H, m), 7.54(1H, d, J=8.5 Hz), 7.59-7.65 (2H, m), 8.14 (1H, br s).

Example 761-{5-tert-Butyl-2-[4-chloro-3-(3-morpholin-4-yl-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 76)

a. Methanesulfonic acid3-[5-(3-tert-butyl-5-{3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triaazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureido}-pyrazol-1-yl)-2-chloro-phenoxy]-propylester (Intermediate 76a)

A mixture of Example 75 (193 mg, 0.27 mmol), methanesulfonyl chloride(63 μL, 0.81 mmol) and DIPEA (200 μL, 1.08 mmol) in DCM (10 mL) wasstirred at RT for 1 h. The volatiles were evaporated under reducedpressure to afford the title compound (214 mg, Quantitative). LCMS(Method 4): Rt 3.57 min, m/z 791 [MH⁺].

b.1-{5-tert-Butyl-2-[4-chloro-3-(3-morpholin-4-yl-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea(Example 76)

A solution of Intermediate 76a (214 mg, 0.27 mmol) and DIPEA (95 μL,0.54 mmol) in THF (5 mL) was treated with morpholine (47 μL, 0.54 mmol).The mixture was stirred at 50° C. for 18 h in a sealed vial. Thevolatiles were concentrated in vacuo and the product was purified byMDAP purification (Method 7) to give the title compound (72 mg, 34%).LCMS (Method 5): Rt 3.60 min, m/z 782.6 [MH⁺]. ¹H NMR (400 MHz,d₆-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77 (4H, m), 1.80-1.94(4H, m), 1.99-2.17 (2H, m), 2.24-2.32 (3H, bs), 2.36-2.42 (2H, t,J=6.9), 3.11-3.17 (4H, m), 3.48-3.52 (4H, m), 4.09-4-15 (2H, t, J=6.52Hz), 4.76-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.03-7.11(2H, m), 7.16 (1H, dd, J=2.0, 9.9 Hz), 7.21-7.41 (5H, m), 7.54 (1H, d,J=8.5 Hz), 7.59-7.65 (2H, m), 8.14 (1H, br s).

Example 771-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt

a.1-(5-tert-Butyl-2-{4-chloro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-{3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 77a)

A mixture of Intermediate 53b (150 mg, 0.26 mmol), and Intermediate B(99 mg, 0.26 mmol) and DIPEA (69 μL, 0.40 mmol) in dioxane (1 mL) washeated at 70° C. for 18 h. The mixture was cooled, diluted with DCM (5mL) and washed with water (2×5 mL). The organic layer was passed througha phase separator and concentrated in vacuo. The residue was purified byFCC, using 0-10% MeOH in DCM, to afford the title compound (154 mg,73%). LCMS (Method 3): Rt: 4.41 min, m/z 797 [MH⁺].

b.1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 77b)

A mixture of Intermediate 77a (150 mg, 0.19 mmol) and pyridiniump-toluene sulfonate (140 mg, 0.56 mmol) in MeOH (1.5 mL) was heated at45° C. for 18 h. The mixture was cooled, diluted with DCM (4 mL) andwashed with saturated aqueous NaHCO₃ solution (2×4 mL). The organiclayer was passed through a phase separator and concentrated in vacuo.The residue was purified by FCC, using 0-10% MeOH:DCM to afford thetitle compound (92 mg, 69%). LCMS (Method 3): Rt: 3.81 min, m/z 713[MH⁺].

c. Methanesulfonic acid2-{5-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-2-chloro-phenoxy}-ethylester (Intermediate 77c)

d.1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy-penyl]-2H-pyrazol-3-yl}-3-{1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt (Example 77)

A mixture of Intermediate 77b (90 mg, 0.13 mmol), methanesulfonylchloride (12 L, 0.15 mmol) and DIPEA (66 μL, 0.38 mmol) in DCM (2 mL)was stirred at RT for 1 h. A further drop of methanesulfonyl chloridewas added and the mixture continued to stir at RT for 30 min. Thereaction mixture was diluted with DCM (2 mL) and washed with water (2×4mL). The organic layer was passed through a phase separator andconcentrated in vacuo to afford Intermediate 77c (LCMS (Method 3): Rt:4.01 min, m/z 791,793 [MH⁺]). This residue (94 mg) was dissolved in THF(2 mL) and treated with dimethylamine solution (2M in THF, 1.5 mL, 3.00mmol). The reaction mixture was heated at 60° C., in a sealed tube for18 h. The mixture was concentrated in vacuo and the residue was purifiedby FCC, using 0-12% 2M NH₃ in MeOH in DCM, to afford a solid. This waspurified by MDAP to afford the title compound (50 mg, 54%). LCMS (Method5): Rt: 3.71 min, m/z 740.5 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 0.91 (3H,d, J=6.3 Hz), 1.28 (9H, s), 1.45-1.56 (2H, m), 1.61-1.74 (2H, m),1.74-1.98 (4H, m), 1.98-2.18 (2H, m), 2.22 (6H, s), 2.67 (2H, t, J=5.7Hz), 2.85-2.95 (11, m, obscured by water), 3.13-3.20 (1H, m, obscured bywater), 3.28-3.36 (11H, m, obscured by water), 4.17 (2H, t, J=5.7 Hz),4.77-4.85 (1H, m), 5.52 (1H, t, J=4.1 Hz), 6.34 (1H, s), 7.07-7.13 (2H,m), 7.19 (1H, dd, J=9.7, 2.1 Hz), 7.23-7.40 (5H, m), 7.54 (1H, d, J=8.5Hz), 7.64 (1H, d, J=9.9 Hz), 7.69 (1H, d, J=2.1 Hz), 8.16 (2.6H, s).

Example 781-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt

a.6-Fluoro-3-((S)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridine(Intermediate 78a)

A mixture of Intermediate Fb (576 mg, 3.36 mmol) and(S)-2-methylpyrrolidine (1.00 g, 11.8 mmol) in DMA (10 mL) was subjectedto microwave irradiation, at 175° C. for 2 h. The reaction mixture wasconcentrated in vacuo and the residue purified by FCC, using 0-15% MeOHin EtOAc, to afford the title compound, which crystallised on standing(357 mg, 48%). LCMS (Method 3): Rt: 2.35 min, m/z 221 [MH⁺].

b.(1S,4R)-4-[3-((S)-2-Methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine(Intermediate 78b)

Intermediate A (318 mg, 1.95 mmol) was dissolved in DMF (1 mL) andsodium hydride (60% dispersion in oil, 125 mg, 3.25 mmol) was addedportionwise. The mixture was stirred at RT for 10 min. A solution ofIntermediate 78a (357 mg, 1.62 mmol) in DMF (1 mL) was added and thereaction mixture was heated at 60° C. for 1.5 h. The mixture was cooledto RT and partitioned between EtOAc (10 mL) and water (10 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by FCC, using 0-10% [2M NH₃ in MeOH] in DCM, toafford the title compound as an orange gum (226 mg, 38%). LCMS (Method3): Rt 0.42, 2.06 min, m/z 364 [MH⁺].

c.1-(5-tert-Butyl-2-{4-chloro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 78c)

A solution of Intermediate 53b (238 mg, 0.41 mmol), Intermediate 78b(220 mg, 0.61 mmol) and DIPEA (158 μL, 0.91 mmol) in dioxane (2.5 mL)was heated at 60° C. for 18 h. The reaction mixture was cooled anddiluted with DCM (5 mL). The organic layer was washed with water (2×5mL), passed through a phase separator and concentrated in vacuo. Theresidue was purified by FCC, using 0-10% [2M NH₃ in MeOH] in DCM, toafford the title compound (62 mg, 19%). LCMS (Method 3): Rt: 4.00 min,m/z 783/785 [MH⁺].

d.1-{5-tert-Butyl-2-[4-chloro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea(Intermediate 78d)

A solution of Intermediate 78c (60.0 mg, 0.08 mmol) and pyridiniump-toluene sulphonate (58.0 mg, 0.23 mmol) in MeOH (1 mL) was heated at45° C. for 18 h. The reaction mixture was cooled and diluted with DCM (5mL). This was washed with sat. aq. NaHCO₃ (2×5 mL). The organic layerwas passed through a phase separator and concentrated in vacuo. Theresidue was purified by FCC, using 0-10% MeOH in DCM, to afford thetitle compound (42 mg, 78%). LCMS (Method 3): Rt: 3.47 min, m/z 699/701[MH⁺].

e. Methanesulfonic acid2-{5-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((S)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-2-chloro-phenoxy}-ethylester (Intermediate 78e)

Methanesulfonyl chloride (5.80 μL, 0.074 mmol) was added to a solutionof Intermediate 78d (40 mg, 0.057 mmol) and DIPEA (30 μL, 0.17 mmol) inDCM (1 mL) and the reaction mixture was stirred at RT for 1 h. Themixture was diluted with DCM (2 mL) and washed with water (2×2 mL). Theorganic layer was passed through a phase separator and concentrated invacuo to afford the title compound (44 mg, 100%). LCMS (Method 3): Rt:3.68 min, m/z 777/779 [MH⁺].

f.1-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt (Example 78)

A solution of Intermediate 78e (44 mg, 0.057 mmol) and dimethylamine (2Min THF, 0.57 mL, 1.14 mmol) in THF (1 mL) was heated at 60° C. for 18 h.The reaction mixture was cooled to RT and the solvent was removed undera stream of air, to leave a residue which was purified by MDAP (Method7), to afford the title compound (16 mg, 38%). LCMS (Method 5): Rt: 3.42min, m/z 726.5 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO): 1.10 (3H, d, J=6.2 Hz),1.28 (9H, s), 1.54-1.65 (1H, m), 1.78-1.95 (3H, m), 1.95-2.08 (2H, m),2.08-2.19 (2H, m), 2.21 (6H, s), 2.65 (2H, t, J=5.6 Hz), 3.09-3.16 (1H,m, obscured by water), 3.80-3.89 (1H, m), 4.06-4.14 (1H, m), 4.16 (2H,t, J=5.6 Hz), 4.75-4.84 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.34 (1H, s),7.04-7.13 (3H, m), 7.22-7.39 (5H, m), 7.52-7.58 (2H, m), 7.79 (1H, d,J=1.9 Hz), 8.15-8.19 (2.2H, m).

Example 791-{5-tert-Butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((R)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt

The title compound was prepared in an analogous fashion to theprocedures described for Example 78, using (R)-2-methylpyrrolidine. LCMS(Method 5): Rt: 3.42 min, m/z 726.5 [MH⁺]. ¹H NMR (400 MHz, d₆-DMSO):1.10 (3H, d, J=6.2 Hz), 1.28 (9H, s), 1.54-1.65 (1H, m), 1.79-2.11 (6H,m), 2.12-2.21 (1H, m), 2.22 (6H, s), 2.67 (2H, t, J=5.6 Hz), 3.10-3.18(1H, m, obscured by water), 3.83-3.91 (1H, m), 4.03-4.13 (1H, m), 4.17(2H, t, J=5.6 Hz), 4.76-4.85 (1H, m), 5.52 (1H, t, J=4.3 Hz), 6.34 (1H,s), 7.06 (1H, dd, J=9.8, 2.1 Hz), 7.08-7.13 (2H, m), 7.22-7.35 (4H, m),7.39 (1H, dd, J=7.4, 1.6 Hz), 7.52-7.58 (2H, m), 7.78 (1H, d, J=1.7 Hz),8.16 (2.4H, s).

Examples 80-87 General Procedure for Table 6—Urea Formation

The compounds synthesised in Table 6 were prepared according to thefollowing general procedure: A mixture of Intermediate LHS (1.0 eq),Intermediate RHS (1.0 eq) and DIPEA (1.2-1.5 eq.) in a suitable solvent(for example 1,4-dioxane, 2-methyltetrahydrofuran or THF) was heated(60-80° C.) for a suitable time until the reaction was complete (e.g.5-24 h). The reaction mixture was cooled, concentrated in vacuo andsubjected to chromatographic purification methods described herein.

TABLE 6 Examples 80-87. Inter- Inter- mediate mediate Ex. used used No.(LHS) (RHS) Example Structure NMR (δ) LCMS 80 Jb E

(400 MHz, d₆-DMSO): 1.27 (9H, s), 1.83-2.23, (8H, m), 2.13 (3H, s), 2.27(6H, s), 2.35 (1H, q, J = 8.6 Hz), 3.13 (1H, m), 3.99 (1H, t, J = 8.2),4.83 (1H, td, J = 8.6, 5.5 Hz), 5.39 (1H, t, J = 4.3 Hz), 6.31 (1H, s),7.09 (1H, d, J = 8.6 Hz), 7.18 (1 H, dd, J = 2.2, 8.1), 7.31-7.29 (7 H,m), 7.75 (1H, dd, J 0.8, 9.9 Hz), 8.00 (1H, s), 8.24 (1H, d, J = 2.1Hz). (Method 5): Rt 3.80 min, m/z 633 [MH⁺]. 81 K E

(400 MHz, d₆-DMSO): 1.26 (9H, s), 1.78-2.10 (7H, m), 1.94 (3H, s), 2.12(3H, s), 2.20 (1H, m), 2.32 (3H, s), 2.35 (1H, q, J = 8.9 Hz), 3.12 (1H,m), 3.98 (1H, t, J = 8.2 Hz), 4.82 (1H, td, J = 5.4, 8.5 Hz), 5.38 (1H,t, J = 4.5 Hz), 6.31 (1H, s), 7.04 (1H, d, J = 8.50 Hz), 7.12 (1H, s),7.21-7.36 (7H, m), 7.74 (1H, dd, J = 0.8, 9.9 Hz), 7.81 (1H, s), 8.23(1H, d, J = 2.1 Hz). (Method 5): Rt 3.77 min, m/z 633 [MH⁺]. 82 Md D

(400 MHz, d₆-DMSO): 1.28 (9H, s), 1.58-1.65 (2H, m), 1.68-1.77 (4H, m),1.81-1.96 (2H, m), 1.98-2.17 (2H, m), 3.11-3.16 (4H, m), 4.60 (2H, brs), 4.76-4.84 (1H, m), 5.49-5.59 (2H, m), 6.33 (1H, s), 7.06 (1H, d, J =8.6 Hz), 7.16 (1H, dd, J = 9.8, 2.1 Hz), 7.24-7.44 (5H, m), 7.52 (1H, d,J = 8.6 Hz), 7.59-7.64 (2H, m), 7.68 (1H, d, J = 2.5 Hz), 8.18 (1H, brs). (Method 5): Rt 4.46 min, m/z 669.2 [MH⁺]. 83 L E

(400 MHz, d₆-DMSO): 1.25 (9H, s), 1.82-1.87 (3H, m), 1.94 (3H, s),1.99-2.03 (2H, m), 2.06- 2.11 (2H, m), 2.12 (3H, s), 2.18-2.22 (1H, m),2.34-2.38 (4H, m), 3.11- 3.13 (1H, m), 3.98 (1H, t, J 8.2), 4.79-4.82(1H, m), 5.38 (1H, t, J = 4.5 Hz), 6.30 (1H, s), 7.04 (1H, d, J 8.5),7.23-7.35 (8H, m), 7.74-7.77 (2H, m), 8.22 (1H, dd, J = 0.9, 2.2 Hz).(Method 5): Rt 3.74 min, m/z 633 [MH⁺]. 84 Ob E

(400 MHz, d₆-DMSO): 1.23 (9H, s), 1.83-2.08 (6H, m), 2.09 (3H, s),2.10-2.19 (2H, m), 2.30- 2.32 (1H, m), 2.40 (4H, t, J = 4.4 Hz), 2.66(2H, td, J = 2.5, 5.7 Hz), 3.08- 3.10 (1H, m), 3.46 (4H, t, J = 4.6 Hz),3.95 (1H, t, J = 8.2 Hz), 4.15 (2H, t, J = 5.7 Hz), 4.75-4.78 (1H, m),5.35 (1H, t, J = 4.2 Hz), 6.30 (1H, s), 7.06 (2H, dd, J = 2.4, 8.5 Hz),7.25-7.37 (6H, m), 7.50 (1H, d, J = 8.5 Hz), 7.71 (1H, dd, J = 0.8, 9.9Hz), 8.10 (1H, s), 8.21 (1H, d, J = 2.1 Hz). (Method 5): Rt 2.81 min,m/z 768 [MH⁺]. 85 Ob D

(400 MHz, d₆-DMSO): 1.27 (9H, s), 1.60-1.64 (2H, m), 1.70-1.76 (4H, m),1.80-1.96 (2H, m), 1.98-2.15 (2H, m), 2.43- 2.46 (4H, m), 2.66-2.74 (2H,m), 3.14 (4H, t, J = 5.2 Hz), 3.50 (4H, t, J = 4.6), 4.19 (2H, t, J =5.7 Hz), 4.80 (1H, t, J = 5.5, 8.6 Hz), 5.54 (1H, t, J = 4.3 Hz), 6.34(1H, s), 7.06-7.16 (3H, m), 7.22- 7.33 (4H, m), 7.37-7.39 (1H, m), 7.53(1H, d, J = 8.5 Hz), 7.61 (1H, dd, J = 0.9, 7.6 Hz), 7.63 (1H, s), 8.14(1H, s). (Method 5): Rt 3.64 min, m/z 768 [MH⁺]. 86 Pd D

(400 MHz, d₆-DMSO): 1.23 (9H, s), 1.54-1.60 (2H, m), 1.64-1.72 (4H, m),1.75-1.95 (2H, m), 1.95-2.10 (2H, m), 2.15 (3H, s), 2.40 (4H, t, J = 4.5Hz), 2.65 (2H, t, J = 5.7 Hz), 3.10 (4H, t, J = 5.3 Hz), 3.47 (4H, t, J= 4.7 Hz), 4.07 (2H, t, J = 5.7 Hz), 4.77 (1H, m), 5.50 (1H, t, J = 4.3Hz), 6.28 (1H, s), 6.91 (1H, dd, J = 2.0, 7.9 Hz), 7.01 (1H, d, J = 2.0Hz), 7.05 (1H, d, J = 8.6 Hz), 7.10 (1H, m), 7.19-7.30 (4H, m), 7.34(1H, d, J = 7.4 Hz), 7.56 (1H, d, J = 8.0 Hz), 7.58 (1H, s), 8.02 (1H,s). (Method 5): Rt 3.70 min, m/z 748.4 [MH⁺]. 87 Sb D

(400 MHz, d₆-DMSO): 1.28 (9H, s), 1.57-1.66 (2H, m), 1.67-1.79 (4H, m),1.84-1.95 (2H, m), 1.98-2.08 (1H, m), 2.10-2.19 (1H, m), 3.14 (4H, t, J= 5.4 Hz), 4.57 (2H, d, J = 4.9 Hz), 4.75-4.85 (1H, m), 5.45 (1H, t, J =5.5 Hz), 5.54 (1H, t, J = 4.2 Hz), 6.32 (1H, s), 7.09 (1H, d, J = 8.6Hz), 7.17 (1H, dd, J = 2.2, 9.6 Hz), 7.24- 7.31 (2H, m), 7.31-7.40 (3H,m), 7.43-7.49 (2H, m), 7.58-7.64 (2H, m), 8.16 (1H, s). (Method 5): Rt4.53 min, m/z 669, 671 [MH⁺].

Biological Assays.

P38alpha Enzyme Inhibition Assay.

The inhibitory activity of compounds was determined using anAlphascreen® (Perkin Elmer) based kinase activity assay. Kinasereactions consisted of 25 mM HEPES pH 7.5, 10 mM MgCl₂, 100 μM Na₃VO₄, 2mM DTT, 0.05 mg/ml Tween 20, 100 pM p38alpha (Invitrogen, PV3304), 1%DMSO and 0.3 μg/ml ATF-2 fusion protein (New England Biolabs, 9224).Compounds were incubated under these conditions for 2 hours, at 25° C.,prior to the initiation of the kinase activity by the addition of the250 μM ATP. Reaction volumes were 20 uL. After 1 hr at 25° C. reactionswere stopped by the adding 10 uL of 25 mM HEPES pH 7.5 containing 62.5mM EDTA, 0.05% Triton X-100, 10% BSA and 0.83 ng/uL anti-phospho-ATF2antibody (Abcam, ab28812). Detection was performed by measuringluminescence following the addition of Alphascreen Donor beads (PerkinElmer 6765300) and Protein A Alphascreen Acceptor beads (Perkin Elmer6760137), both at a final concentration of 20 ug/ml. IC₅₀ values weredetermined from concentration-response curves.

All the compounds of the invention have a p38□ binding potency less than10 nM.

LPS-Stimulated PBMC TNFα Release Assay.

Peripheral Blood Mononuclear Cells (PBMCs) were isolated from healthyhuman volunteer blood using a standard density gradient centrifugationtechnique. Citrated blood was placed onto Histopaque™ and centrifuged.The PBMCs were removed from the density gradient interface and washed inphosphate buffered saline (PBS). The PBMCs were suspended in RPMI 1640medium (without serum), dispensed into a 96-well plate and incubated at37° C. for 3 h in a humidified incubator. After incubation, the mediumwas replaced (with medium containing 1% foetal bovine serum) and theplate incubated at 37° C., for 1 h, in the presence of test compound orthe appropriate vehicle. LPS (10 ng/ml), or an appropriate vehiclecontrol, was then added to the cells and the plate returned to theincubator for 18 h. Cell-free supernatants were removed and assayed forTNFα levels using an ELISA kit from R&D Systems.

A dose response curve to each test compound was performed and the effectof compound in each experiment was expressed as a percentage inhibitionof the control TNFα release. Dose response curves were plotted andcompound potency (IC₅₀) was determined. Compounds were tested in atleast three separate experiments.

All the compounds of the invention show p38□ potencies (IC₅₀ values)lower than 10 nM.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein W is a N or O, wherein N is substituted with —H, C₁-C₆ alkyl orC₃-C₅ cycloalkyl; Y is a group —S(O)_(p)— wherein p is 0, 1 or 2; agroup —O(CR³R⁴)_(n)—; a group —(CR⁵R⁶)_(n)—; a group —NR⁷—; a group—OC(O)—; a group —OC(O)NH—; or a group —OC(O)O—; R³, R⁴, R⁵ and R⁶ areeach independently —H, —F or C₁-C₆ alkyl, or, respectively, R³ and R⁴,or R⁵ and R⁶ may form together with the carbon atom to which they areattached a saturated 3-6 membered carbocyclic monocyclic ring optionallysubstituted by a group C₁-C₆ alkyl, hydroxyl or halo; n is 0, 1,2 or 3;R⁷ is —H, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl wherein said C₁-C₆ alkyl orC₃-C₇ cycloalkyl are optionally substituted by a group C₁-C₃ alkyl,C₃-C₆ cycloalkyl, hydroxyl, —CN or halo; R¹ is a group selected from(IIa)-(IIc):

R⁸ and R⁹ are each independently —H or C₁-C₆ alkyl, or R⁸ and R⁹ mayform together with the nitrogen atom to which they are attached a4-11-membered saturated monocyclic or a fused or spiro bicyclic ringsystem optionally containing a further heteroatom which is oxygen ornitrogen, said nitrogen atom being optionally substituted by C₁-C₆alkyl; wherein said C₁-C₆ alkyl groups may be optionally substituted bya group C₁-C₆ alkyl, C₃-C₆ cycloalkyl, hydroxyl or halo; X¹, X², X³, X⁴and X⁵ are each independently a carbon atom, a nitrogen atom, a group—(CH)— or a group —NH—; such that each combination thereof forms anaromatic ring system; R¹⁰ is selected from the group consisting of —H,—CN, —NR^(A)R^(B), —N(R^(C))(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))(C₃-C₇cycloalkylene)-NR^(A)R^(B), —(C₁-C₆alkylene)-NR^(A)R^(B),—(C₃-C₇cycloalkylene)-NR^(A)R^(B), —O—(C₂-C₆alkylene)-NR^(A)R^(B),—O—(C₃-C₇cycloalkylene)-NR^(A)R^(B), —S—(C₂-C₆alkylene)-NR^(A)R^(B),—S—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B)—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—C(O)N(R^(C))—(C₂-C₆alkylene)-OR^(D),—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D), —N(R^(C))C(O)NR^(A)R^(B),—C(O)NR^(A)R^(B), —N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—(C₂-C₆alkylene)-OR^(D), —(C₃-C₇cycloalkylene)-OR^(D),—O—(C₂-C₆alkylene)-OR^(D), —O—(C₃-C₇cycloalkylene)-OR^(D),—S—(C₂-C₆alkylene)-OR^(D), —S—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))S(O)₂—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-OR^(D),—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D),—N(R^(C))S(O)₂—(C₂-C₆alkylene)-OR^(D),—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-OR^(D), —S(O)₂N(R^(A)R^(B)),—N(R^(C))S(O)₂R^(D), —N(R^(C))C(O)R^(C), —OR^(C), —SR^(C),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl),(C₅-C₇heterocycloalkyl)(C₃-C₆cycloalkyl)-, andC₃-C₇heterocycloalkylcarbonyl; wherein any of said C₁-C₆alkyl,C₃-C₆cycloalkyl, —(C₁-C₆alkylene)- —(C₂-C₆alkylene)-,—(C₃-C₇cycloalkylene)-, —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) and (C₃-C₇heterocycloalkyl)carbonyl portion in the abovelisted groups may be optionally substituted by a group C₁-C₆ alkyl,C₃-C₇ cycloalkyl, hydroxyl or halo; R¹¹ is linked to X⁴ and is selectedfrom the group consisting of —H; —CN; C₁-C₆ alkyl which is substitutedby a group selected from the group consisting of —CN, —OR^(C), —SR^(C),and halo; C₃-C₆cycloalkyl which is substituted by a group selected fromthe group consisting of C₁-C₄ alkyl, —CN, —OR^(C), —SR^(D), and halo;—NR^(A)R^(B); —N(R^(C))(C₂-C₆alkylene)-NR^(A)R^(B);—N(R^(C))(C₃-C₇cycloalkylene)-NR^(A)R^(B); —(C₁-C₆alkylene)-NR^(A)R^(B);—(C₃-C₇cycloalkylene)-NR^(A)R^(B); —O—(C₂-C₆alkylene)-NR^(A)R^(B);—O—(C₃-C₇cycloalkylene)-NR^(A)R^(B); —S—(C₂-C₆alkylene)-NR^(A)R^(B);—S—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B);—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B);—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—C(O)N(R^(C))—(C₂-C₆alkylene)-OR^(D);—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D); —N(R^(C))C(O)N(R^(A)R^(B)),—C(O)N(R^(A)R^(B)); —N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B);—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—O—(C₂-C₆alkylene)-OR^(D); —O—(C₃-C₇cycloalkylene)-OR^(D);—S—(C₂-C₆alkylene)-OR^(D); —S—(C₃-C₇cycloalkylene)-OR^(D);—N(R^(C))S(O)₂—(C₁-C₆alkylene)-NR^(A)R^(B);—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—S(O)₂N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B);—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—S(O)₂N(R^(C))—(C₂-C₆alkylene)-OR^(D);—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D);—N(R^(C))S(O)₂—(C₂-C₆alkylene)-OR^(D);—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-OR^(D); —S(O)₂N(R^(A)R^(B));—N(R^(C))S(O)₂R^(D); —N(R^(C))C(O)R^(C); OR^(C); SR^(C);—(C₃-C₇heterocycloalkyl); (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl);(C₅-C₇heterocycloalkyl)(C₃-C₆cycloalkyl); and (C₃-C₇heterocycloalkyl)carbonyl, wherein any of said C₁-C₆alkyl,C₃-C₆cycloalkyl, —(C₁-C₆alkylene)- —(C₂-C₆alkylene)-,—(C₃-C₇cycloalkylene)-, —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) and (C₃-C₇heterocycloalkyl)carbonyl portion in the abovelisted groups may be optionally substituted by one, two or three groupsR²⁵ which are independently selected from the group consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl, —CN, OR^(D) and halo; or R¹¹ is linked to X⁴ and is phenyl or5- or 6-membered monocyclic heteroaryl, wherein said phenyl or 5- or6-membered monocyclic heteroaryl is substituted by a group selected fromthe group consisting of C₁-C₆ alkyl which is substituted by a group —CN;C₃-C₆ cycloalkyl which is substituted by a group selected from the groupconsisting of —CN, —OR^(C), —SR^(C) and halo;—N(R^(C))(C₂-C₆alkylene)-NR^(A)R^(B);—N(R^(C))(C₃-C₇cycloalkylene)-NR^(A)R^(B); —(C₁-C₆alkylene)-NR^(A)R^(B);—(C₃-C₇cycloalkylene)-NR^(A)R^(B); —O—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—S—(C₂-C₆alkylene)-NR^(A)R^(B); —S—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B);—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B);—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—C(O)N(R^(C))—(C₂-C₆alkylene)-OR^(D);—C(O)N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D);—N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B);—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—O—(C₃-C₇cycloalkylene)-OR^(D); —S—(C₃-C₇cycloalkylene)-OR^(D);—N(R^(C))S(O)₂—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—S(O)₂N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B);—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B);—S(O)₂N(R^(C))—(C₂-C₆alkylene)-OR^(D);—S(O)₂N(R^(C))—(C₃-C₇cycloalkylene)-OR^(D);—N(R^(C))S(O)₂—(C₂-C₆alkylene)-OR^(D);—N(R^(C))S(O)₂—(C₃-C₇cycloalkylene)-OR^(D); —N(R^(C))S(O)₂R^(D);—(C₃-C₇heterocycloalkyl); (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl);(C₅-C₇heterocycloalkyl)(C₃-C₆cycloalkyl); and(C₃-C₇heterocycloalkyl)carbonyl, wherein any of said C₁-C₆alkyl,C₃-C₆cycloalkyl, —(C₁-C₆alkylene)- —(C₂-C₆alkylene)-,—(C₃-C₇cycloalkylene)-, —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl), (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) and (C₃-C₇heterocycloalkyl)carbonyl portion in the abovelisted groups may be optionally substituted by one, two or three groupsR²⁵ which are independently selected from the group consisting ofC₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇cycloalkyl,hydroxyl, —CN, OR^(D) and halo; R^(A) and R^(B) are at each occurrenceindependently —H, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl andC₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,C₃-C₇cycloalkyl, —OR^(D), —CN or halo; alternatively, R^(A) and R^(B),may form together with the nitrogen atom to which they are attached anazetidine or a 4-11-membered saturated heterocyclic monocyclic orbicyclic ring system which is optionally substituted by one or moregroup —OR^(D), —CN, halo, C₁-C₆ alkyl, (C₁-C₆)hydroxyalkyl or C₃-C₇cycloalkyl, said C₁-C₆ alkyl and C₃-C₇ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(D), —CN orhalo; and which 6-11-membered saturated heterocyclic monocyclic orbicyclic ring optionally contains a further heteroatom which is oxygenor nitrogen, said nitrogen atom optionally substituted by C₁-C₆ alkyl orC₃-C₆ cycloalkyl, wherein any of said C₁-C₆ alkyl or C₃-C₆ cycloalkylmay be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(D), —CN, or halo; or R^(A) and R^(B) may be linked to one carbonatom of the —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)- or—(C₃-C₇cycloalkylene)- portion of the group linked to the nitrogen towhich they are connected to form a saturated cycle of up to 6 ringatoms; R^(C) is at each occurrence independently —H, C₁-C₆ alkyl,(C₁-C₄)hydroxyalkyl or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl and C₃-C₆cycloalkyl being optionally substituted by a group C₁-C₃ alkyl, —OR^(D),—CN or halo; alternatively R^(C) may be linked to one carbon atom of the—(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)- portion of the group linkedto the nitrogen to which they are connected to form a saturated cycle ofup to 6 ring atoms R^(D) is at each occurrence independently —H, —CH₃ or—C₂H₅; R¹² and R¹³ are independently —H, C₁-C₆ alkyl, or halogen; A is adivalent cycloalkylene radical having 5, 6 or 7 ring atoms; saidcycloalkylene ring being attached to W and Y and fused to a phenyl ringor to a monocyclic heteroaryl ring having 5 or 6 ring atoms, said phenylor heteroaryl ring being optionally substituted by one or two groupsR²⁴; R²⁴ is at each occurrence independently selected from the groupconsisting of C₁-C₆ alkyl, halogen and —CN; R² is a radical of formula(IIIb):

wherein R¹⁷ is selected from the group consisting of a lone electronpair, —H, —CF₃, —NR^(E)R^(F), —(C₃-C₇cycloalkyl),—(C₃-C₇heterocycloalkyl), aryl or heteroaryl wherein any of said—(C₃-C₇cycloalkyl), —(C₃-C₇heterocycloalkyl), aryl or heteroaryl may beoptionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl or halo;or R¹⁷ is a group of general formula (IV)

wherein R²⁰ is selected in the group consisting of —F, —CH₃, —C₂H₅,—CH₂OH, —CH₂OMe, —CF₂CF₃, —CH₂SCH₃, —SCH₃ and —SC₂H₅; R²¹ is —CH₃ or—C₂H₅; or R²⁰ and R²¹ as defined above may form together with the carbonatom to which they are attached a saturated 3-7-membered monocyclicring; R^(E) and R^(F) are each independently C₁-C₆ alkyl, optionallysubstituted by a group C₁-C₃ alkyl, —OR^(G), —CN or halo; alternativelyR^(E) and R^(F) may form together with the nitrogen atom to which theyare attached a 5-11-membered saturated monocyclic or bicyclicheterocyclic ring system which is optionally substituted by one or moregroups —OR^(G), —CN, halo, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, said C₁-C₆alkyl and C₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃alkyl, C₃-C₇cycloalkyl, —OR^(G), —CN or halo; and which 5-11-memberedsaturated monocyclic or bicyclic heterocyclic ring optionally contains afurther heteroatom which is oxygen or nitrogen, said nitrogen atomoptionally substituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein anyof such C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionally substituted bya group C₁-C₆ alkyl or C₃-C₇ cycloalkyl; R^(G) is —H, —CH₃ or —C₂H₅; R¹⁸is selected from the group consisting of aryl, heterocycloalkyl andheteroaryl, wherein any of said aryl, heterocycloalkyl or heteroaryl issubstituted by two or more groups independently selected from the groupconsisting of —CN, —OH, ═O, halo, —COOR^(M), C₁-C₆ alkyl,C₃-C₆cycloalkyl, —O—(C₁-C₆alkyl), —(C₁-C₆)hydroxyalkyl,—O—(C₃-C₆cycloalkyl), —S—(C₁-C₆alkyl), —S—(C₃-C₆cycloalkyl),—NR^(H)R^(J), —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —S—(C₂-C₆alkylene)-NR^(H)R^(J),—S—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—C(O)N(R^(L))—(C₂-C₆alkylene)-OR^(M),—C(O)N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M), —N(R^(L))C(O)N(R^(H)R^(J),—C(O)N(R^(H)R^(J)), —N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), —S—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—S(O)₂N(R^(L))—(C₂-C₆alkylene)-OR^(M),—S(O)₂N(R^(L))—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-OR^(M), —S(O)₂N(R^(H)R^(J)),—N(R^(L))S(O)₂R^(L), —N(R^(L))C(O)R^(L), OR^(L), SR^(L),—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl) and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl), wherein any of saidC₁-C₆alkyl, C₃-C₆cycloalkyl, —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)-,—(C₃-C₇cycloalkylene)-, —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl) and (C₅-C₇heterocycloalkyl)-(C₃-C₆ cycloalkyl) portion in the above listed groupsmay be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl,—OR^(L) or halo; R^(H) and R^(J) are at each occurrence independently—H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl or C₃-C₆cycloalkyl being optionally substituted by a group C₁-C₃ alkyl, —OR^(M),CN or halo; alternatively, R^(H) and R may also form together with thenitrogen atom to which they are attached a 4-11-membered saturatedmonocyclic or bicyclic heterocyclic ring system which is optionallysubstituted by one or more groups —OR^(M), —CN, halo, NR^(O)R^(P), C₁-C₆alkyl or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl and C₃-C₇ cycloalkyl beingoptionally substituted by a group C₁-C₃ alkyl, C₃-C₇cycloalkyl, —OR^(M),CN or halo; and which 6-11-membered saturated monocyclic or bicyclicheterocyclic ring optionally contains a further heteroatom which isoxygen or nitrogen, said nitrogen atom optionally substituted by C₁-C₆alkyl or C₃-C₆ cycloalkyl, wherein any of said C₁-C₆ alkyl or C₃-C₆cycloalkyl may be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇cycloalkyl, —OR^(M), CN, or halo; or R^(H) and R^(J) may be linked toone carbon atom of the —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)- or—(C₃-C₇cycloalkylene)- portion of the group linked to the nitrogen towhich they are connected to form a saturated cycle of up to 6 ringatoms; R^(L) is at each occurrence independently —H, C₁-C₆ alkyl orC₃-C₆ cycloalkyl, said C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), —CN or halo; R^(M) is ateach occurrence independently —H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, saidC₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionally substituted by a grouphydroxyl, —CN or halo; R^(O) and R^(P) are each independently C₁-C₆alkyl or C₁-C₆ cycloalkyl, optionally substituted by a group C₁-C₃alkyl, —OR^(Q), —CN or halo; alternatively, R^(O) and R^(P) may formtogether with the nitrogen atom to which they are attached a4-8-membered saturated monocyclic heterocyclic ring system which isoptionally substituted by one or more groups —OR^(Q), —CN, halo, C₁-C₆alkyl or C₃-C₇ cycloalkyl, and which 4-8-membered saturated monocyclicheterocyclic ring optionally contains a further heteroatom which isoxygen or nitrogen, said nitrogen atom optionally substituted by C₁-C₆alkyl or C₃-C₆ cycloalkyl; R^(Q) is —H, —CH₃ or —C₂H₅; z¹, z², z³, andz⁴ are independently selected from the group consisting of C, N, S, O, agroup —CH— and a group —NH—, in such a combination that the resultingring formed is an aromatic system; with the proviso that when Y is agroup —O(CR³R⁴)_(n)—, n is 1 and R¹⁰ is —NR^(A)R^(B),—N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(A)R^(B)),—N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B) or—N(R^(C))C(O)R^(C), then X₁ is nitrogen.
 2. A compound orpharmaceutically acceptable salt according to claim 1, wherein W is Nsubstituted with —H, C₁-C₆ alkyl or C₃-C₅ cycloalkyl; Y is—O(CR³R⁴)_(n)—; R³ and R⁴ are each independently —H, —F or C₁-C₆ alkyl;n is 0, 1, 2 or 3; R¹ is a group (IIc)

X², X³, X⁴ and X⁵ are each independently a carbon atom, a nitrogen atom,a group —(CH)— or a group —NH—; such that each combination thereof formsan aromatic ring system; R¹¹ is linked to X⁴ and is selected from thegroup consisting of —NR^(A)R^(B), —N(R^(C))(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))(C₃-C₇cycloalkylene)-NR^(A)R^(B), —(C₁-C₆alkylene)-NR^(A)R^(B),and —(C₃-C₇cycloalkylene)-NR^(A)R^(B) wherein any of said—(C₂-C₆alkylene)- and —(C₃-C₇cycloalkylene)- portion in the above listedgroups may be optionally substituted by one, two or three groups R²⁵which are independently selected from the group consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl, —CN, OR^(D) and halo; R^(A) and R^(B) may form together withthe nitrogen atom to which they are attached an azetidine or a4-11-membered saturated heterocyclic monocyclic ring system which isoptionally substituted by one or more group —OR^(D), —CN, halo, C₁-C₆alkyl, (C₁-C₆)hydroxyalkyl or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl andC₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,C₃-C₇cycloalkyl, —OR^(D), —CN or halo; and which 6-11-membered saturatedheterocyclic monocyclic or bicyclic ring optionally contains a furtherheteroatom which is oxygen or nitrogen, said nitrogen atom optionallysubstituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein any of saidC₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionally substituted by a groupC₁-C₆ alkyl, C₃-C₇ cycloalkyl, —OR^(D), —CN, or halo; or R^(A) and R^(B)may be linked to one carbon atom of the —(C₁-C₆alkylene)-,—(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)-portion of the group linkedto the nitrogen to which they are connected to form a saturated cycle ofup to 6 ring atoms; R^(C) is at each occurrence independently —H, C₁-C₆alkyl, (C₁-C₄)hydroxyalkyl or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl andC₃-C₆ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,—OR^(D), —CN or halo; alternatively R^(C) may be linked to one carbonatom of the —(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)- portion of thegroup linked to the nitrogen to which they are connected to form asaturated cycle of up to 6 ring atoms; R^(D) is at each occurrenceindependently —H, —CH₃ or —C₂H₅; R¹² and R¹³ are independently —H, C₁-C₆alkyl or halogen; A is a divalent cycloalkylene radical having 5, 6 or 7ring atoms; said cycloalkylene ring being attached to W and Y, and fusedto a phenyl ring or to a monocyclic heteroaryl ring having 5 or 6 ringatoms, said phenyl or heteroaryl ring being optionally substituted byone or two groups R²⁴; R²⁴ is at each occurrence independently selectedfrom the group consisting of C₁-C₆ alkyl, halogen and —CN; R² is aradical of formula (IIIb)

wherein R¹⁷ is a group of general formula (IV)

wherein R²⁰ is selected from the group consisting of —F, —CH₃, —C₂H₅,—CH₂OH, —CH₂OMe, —CF₂CF₃, —CH₂SCH₃, —SCH₃ and —SC₂H₅; R²¹ is —CH₃ or—C₂H₅; or R²⁰ and R²¹ as defined above may form together with the carbonatom to which they are attached a saturated 3-7-membered monocyclicring; R¹⁸ is selected from the group consisting of aryl,heterocycloalkyl and heteroaryl, wherein any of said aryl,heterocycloalkyl or heteroaryl is substituted by two or more groupsindependently selected from —CN, —OH, ═O, halo, —COOR^(M), C₁-C₆ alkyl,C₃-C₆cycloalkyl, —O—(C₁-C₆alkyl), —(C₁-C₆)hydroxyalkyl,—O—(C₃-C₆cycloalkyl), —NR^(H)R^(J),—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))(C₃-C₇cycloalkylene)-NR^(H)R^(J), —(C₁-C₆alkylene)-NR^(H)R^(J),—(C₃-C₇cycloalkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-NR^(H)R^(J),—O—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(H)R^(J)),—N(R^(L))C(O)N(R^(L))—(C₂-C₆alkylene)-NR^(H)R^(J),—N(R^(L))C(O)N(R^(L))—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-OR^(M), —O—(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))S(O)₂—(C₁-C₆alkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₃-C₇cycloalkylene)-NR^(H)R^(J),—N(R^(L))S(O)₂—(C₂-C₆alkylene)-OR^(M), —(C₃-C₇cycloalkylene)-OR^(M),—N(R^(L))C(O)R^(L), OR^(L), —(C₃-C₇heterocycloalkyl),(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) and (C₅-C₇heterocycloalkyl)-(C₃-C₆cycloalkyl), wherein any of said C₁-C₆alkyl, C₃-C₆cycloalkyl,—(C₁-C₆alkylene)-, —(C₂-C₆alkylene)-, —(C₃-C₇cycloalkylene)-,—(C₃-C₇heterocycloalkyl), (C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl) portion in the above listedgroups may be optionally substituted by a group C₁-C₆ alkyl, C₃-C₇cycloalkyl, —OR^(L) or halo; R^(H) and R^(J) are at each occurrenceindependently —H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl orC₃-C₆ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,—OR^(M), CN or halo; alternatively, R^(H) and R^(J) may also formtogether with the nitrogen atom to which they are attached a4-11-membered saturated monocyclic or bicyclic heterocyclic ring systemwhich is optionally substituted by one or more groups —OR^(M), —CN,halo, NR^(O)R^(P), C₁-C₆ alkyl or C₃-C₇ cycloalkyl, said C₁-C₆ alkyl andC₃-C₇ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,C₃-C₇cycloalkyl, —OR^(M), CN or halo; and which 6-11-membered saturatedmonocyclic or bicyclic heterocyclic ring optionally contains a furtherheteroatom which is oxygen or nitrogen, said nitrogen atom optionallysubstituted by C₁-C₆ alkyl or C₃-C₆ cycloalkyl, wherein any of suchC₁-C₆ alkyl or C₃-C₆ cycloalkyl may be optionally substituted by a groupC₁-C₆ alkyl, C₃-C₇ cycloalkyl, —OR^(M), CN, or halo; or R^(H) and R^(J)may be linked to one carbon atom of the —(C₁-C₆alkylene)-,—(C₂-C₆alkylene)- or —(C₃-C₇cycloalkylene)- portion of the group linkedto the nitrogen to which they are connected to form a saturated cycle ofup to 6 ring atoms; R^(L) is at each occurrence independently —H, C₁-C₆alkyl or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl or C₃-C₆cycloalkyl beingoptionally substituted by a group C₁-C₃ alkyl, —OR^(M), —CN or halo;R^(M) is at each occurrence independently —H, C₁-C₆ alkyl or C₃-C₆cycloalkyl, said C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group hydroxyl, —CN or halo; R^(O) and R^(P) are eachindependently C₁-C₆ alkyl or C₁-C₆ cycloalkyl, optionally substituted bya group C₁-C₃ alkyl, —OR^(Q), —CN or halo; alternatively, R^(O) andR^(P) may form together with the nitrogen atom to which they areattached a 4-8-membered saturated monocyclic heterocyclic ring systemwhich is optionally substituted by one or more groups —OR^(Q), —CN,halo, C₁-C₆ alkyl or C₃-C₇ cycloalkyl, and which 4-8-membered saturatedmonocyclic heterocyclic ring optionally contains a further heteroatomwhich is oxygen or nitrogen, said nitrogen atom optionally substitutedby C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R^(Q) is —H, —CH₃ or —C₂H₅; z¹, z²,z³, and z⁴ are independently selected from the group consisting of: C,N, S, O, a group —CH—, and a group —NH—, in such a combination that theresulting ring formed is an aromatic system; with the proviso that whenY is a group —O(CR³R⁴)_(n)—, n is 1 and R^(1′) is —NR^(A)R^(B),—N(R^(C))C(O)—(C₁-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)—(C₃-C₇cycloalkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(A)R^(B)),—N(R^(C))C(O)N(R^(C))—(C₂-C₆alkylene)-NR^(A)R^(B),—N(R^(C))C(O)N(R^(C))—(C₃-C₇cycloalkylene)-NR^(A)R^(B) or—N(R^(C))C(O)R^(C), then X₁ is nitrogen.
 3. A compound orpharmaceutically acceptable salt according to claim 1, wherein W is NH,Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group

wherein R¹ is a group of formula (IIca) which is connected to the groupY through the carbon adjacent to X²

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H; wherein R¹¹ is a group:

wherein R²⁵ is optionally present and represents one, two or threesubstituents independently selected from the group consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl and halo; and wherein the asterisk represents the point ofattachment for group R¹¹ to the rest of the molecule via X⁴; wherein R²is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of formula(IV)

wherein R²⁰ and R²¹ are —CH₃ and wherein R¹⁸ is aryl substituted by twoor more groups independently selected from the group consisting of —CN,—OH, halo, —COOR^(M), C₁-C₆alkyl, —O—(C₁-C₆alkyl), —(C₁-C₆)hydroxyalkyl,—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J), (C₁-C₆alkylene)-NR^(H)R^(J),—O—(C₂-C₆alkylene)-NR^(H)R^(J), —O—(C₂-C₆alkylene)-OR^(M),—S—(C₂-C₆alkylene)-OR^(M), (C₅-C₇heterocycloalkyl)-(C₁-C₆ alkyl) and(C₅-C₇ heterocycloalkyl)-(C₃-C₆ cycloalkyl) wherein any of saidC₁-C₆alkyl, —(C₁-C₆alkylene)-, —(C₂-C₆alkylene)-,(C₅-C₇heterocycloalkyl)-(C₁-C₆alkyl) and (C₅-C₇ heterocycloalkyl)-(C₃-C₆cycloalkyl) portion may be optionally substituted by a group C₁-C₆alkyl, C₃-C₇ cycloalkyl, OR^(L) or halo; wherein R^(H) and R^(J) areindependently —H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, said C₁-C₆ alkyl orC₃-C₆ cycloalkyl being optionally substituted by a group C₁-C₃ alkyl,—OR^(M), CN or halo; or R^(H) and R^(J) may form together with thenitrogen atom to which they are attached a 4-11-membered saturatedmonocyclic or bicyclic heterocyclic ring system which is optionallysubstituted by one or more C₁-C₆alkyl and which 4-11-membered saturatedmonocyclic or bicyclic heterocyclic ring optionally contain a furtherheteroatom which is oxygen or nitrogen and R^(M) is —H.
 4. A compound orpharmaceutically acceptable sailt according to claim 1, wherein W is NH,Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group

wherein R¹ is a group of formula (IIca) which is connected to the groupY through the carbon adjacent to X²

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H; R¹¹ is a group

wherein R²⁵ is optionally present and represents one, two or threesubstituents independently selected from the group consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl and halo; and wherein the asterisk represents the point ofattachment for group R¹¹ to the rest of the molecule via X⁴; R² is aradical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of formula(IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is a phenyl substituted by two ormore groups independently selected from the group consisting of —OH,halo, C₁-C₆alkyl, (C₁-C₆)hydroxyalkyl, —O—(C₂-C₆alkylene)-NR^(H)R^(J)and —(C₁-C₆alkylene)-NR^(H)R^(J), wherein any of such C₁-C₆alkyl,—(C₁-C₆alkylene)- and —(C₂-C₆alkylene)- portion may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl, OR^(L) or halo;wherein R^(H) and R^(J) are independently —H, C₁-C₆ alkyl or C₃-C₆cycloalkyl, said C₁-C₆ alkyl or C₃-C₆ cycloalkyl being optionallysubstituted by a group C₁-C₃ alkyl, —OR^(M), CN or halo; or R^(H) andR^(J) may form together with the nitrogen atom to which they areattached a 4-11-membered saturated monocyclic or bicyclic heterocyclicring system which is optionally substituted by one or more C₁-C₆alkyland which 4-11-membered saturated monocyclic or bicyclic heterocyclicring optionally contain a further heteroatom which is oxygen or nitrogenand R^(M) is —H.
 5. A compound or pharmaceutically acceptable saltaccording to claim 1, wherein W is NH, Y is a group —O(CR³R⁴)_(n)— and nis 0, A is group

R¹ is a group of formula (IIca) which is connected to t e group Ythrough the carbon adjacent to X₂

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H; wherein R¹ is a group

wherein R²⁵ is optionally present and represents one two or threesubstituents independently selected from the group consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl and halo; and wherein the asterisk represents the point ofattachment for group R¹¹ to the rest of the molecule via X⁴; wherein R²is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of formula(IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is a 5 or 6-membered heteroarylwhich is substituted by two or more groups independently selected fromthe group consisting of C₁-C₆alkyl, —(C₁-C₆)hydroxyalkyl,—N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J) and —(C₁-C₆alkylene)-NR^(H)R^(J),wherein any of said C₁-C₆alkyl, —(C₁-C₆alkylene)- and —(C₂-C₆alkylene)-portion in the above listed groups may be optionally substituted by agroup C₁-C₆ alkyl, C₃-C₇ cycloalkyl OR^(L) or halo.
 6. A compound orpharmaceutically acceptable salt according to claim 1, wherein W is NH,Y is a group —O(CR³R⁴)_(n)— and n is 0, A is group

wherein R¹ is a group of formula (IIca) which is connected to the groupY through the carbon adjacent to X₂

and wherein X⁴ is a carbon atom, X⁵ is a nitrogen atom, X³ is a nitrogenatom and X² is a group —CH—, and R¹³ is —H; wherein R¹¹ is a group

wherein R²⁵ is optionally present and represents one two or threesubstituents independently selected from the group consisting of C₁-C₆alkyl, (C₁-C₃) haloalkyl, (C₁-C₄)hydroxyalkyl, C₃-C₇ cycloalkyl,hydroxyl and halo; and wherein the asterisk represents the point ofattachment for group R¹¹ to the rest of the molecule via X⁴; wherein R²is a radical of formula (IIIb)

wherein z¹=—CH—, z²=C, z³ and z⁴ are N and R¹⁷ is a group of formula(IV)

wherein R²⁰ and R²¹ are —CH₃ and R¹⁸ is a heterocycloalkyl substitutedby two or more groups independently selected from the group consistingof ═O, C₁-C₆alkyl, —N(R^(L))(C₂-C₆alkylene)-NR^(H)R^(J) or—(C₁-C₆alkylene)-NR^(H)R^(J), wherein any of said C₁-C₆alkyl and—(C₁-C₆alkylene)- portion in the above listed groups may be optionallysubstituted by a group C₁-C₆ alkyl, C₃-C₇ cycloalkyl OR^(L) or halo. 7.A compound or pharmaceutically acceptable salt according to claim 1,which is selected from the group consisting of1-[5-tert-butyl-2-(2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl)}urea;1-[5-tert-butyl-2-(2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylurea formate salt;1-{5-tert-butyl-2-[5-(2-dimethylamino-ethoxy)-2-fluoro-phenyl]-2H-pyrazol-3-yl}-3-((1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[5-(2-dimethylamino-ethoxy)-2-fluoro-phenyl]-2H-pyrazol-3-yl)}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(4-chloro-3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}1-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-(2-diethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-methyl-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt;1-{5-tert-butyl-2-[3-(2-dimethylamino-ethoxy)-4-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[3-chloro-5-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt;1-[5-tert-butyl-2-(3-chloro-5-piperidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[3-chloro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[2-chloro-5-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt;1-[5-tert-butyl-2-(3-fluoro-5-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[3-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[3-(2-dimethylamino-ethoxy)-5-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(3-fluoro-5-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[3-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[3-(2-dimethylamino-ethoxy)-5-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-cyano-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt;1-(5-tert-butyl-2-{4-chloro-3-[2-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazol-3-yl)}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl)}-ureaformate salt;1-(5-tert-butyl-2-{4-chloro-3-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-(5-tert-butyl-2-{4-fluoro-3-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl)}-ureaformate salt;1-{2-[3-(2-azetidin-1-yl-ethyl)-4-fluoro-phenyl]-5-tert-butyl-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-(5-tert-butyl-2-{3-[2-(3-dimethylamino-azetidin-1-yl)-ethyl]-4-fluoro-phenyl}-2H-pyrazol-3-yl)-3-(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[3-(2-dimethylamino-ethyl)-4-fluoro-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(4-chloro-3-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(4-chloro-3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(4-chloro-3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(4-fluoro-3-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-fluoro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(4-fluoro-3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;1-[5-tert-butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;1-[5-tert-butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-hydroxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl}-urea;1-{5-tert-butyl-2-[4-chloro-3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(3-hydroxy-5-methyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[3-(2-dimethylamino-ethoxy)-4-hydroxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-hydroxymethyl-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt;1-(5-tert-butyl-2-{4-hydroxymethyl-3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[3-(2-dimethylamino-ethoxy)-4-hydroxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;1-{5-tert-butyl-2-[4-hydroxymethyl-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaformate salt;1-(5-tert-butyl-2-{4-hydroxymethyl-3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(3-chloro-5-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;1-[5-tert-butyl-2-(3-chloro-5-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(4-chloro-3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-[1,4]oxazepan-4-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(4-chloro-3-piperidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(4-chloro-3-pyrrolidin-1-ylmethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[1-(2-dimethylamino-ethyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(piperidin-4-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-((R)-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-((S)-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-((R)-1-methyl-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-((S)-1-methyl-piperidin-3-yloxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[3-tert-butyl-1′-(2-dimethylamino-ethyl)-3′-hydroxymethyl-1′H-[1,4′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-(3-morpholin-4-yl-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-(3-morpholin-4-yl-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-{5-tert-butyl-2-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((R)-2-methyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaformate salt;1-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;1-[5-tert-butyl-2-(2,5-dimethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;1-[5-tert-butyl-2-(4-chloro-3-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(2,4-dimethyl-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;1-{5-tert-butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;1-{5-tert-butyl-2-[4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-{5-tert-butyl-2-[4-methyl-3-(2-morpholin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[5-tert-butyl-2-(3-chloro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea;1-[3-tert-butyl-1′-(2-dimethylamino-ethyl)-4′-hydroxymethyl-1′H-[1,3′]bipyrazolyl-5-yl]-3-{((1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;and1-[5-tert-butyl-2-(3,5-dimethyl-isoxazol-4-yl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureaor pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition, comprising a compound or pharmaceutically acceptable saltas claimed in claim 1 and one or more pharmaceutically acceptablecarriers.
 9. A method of treating a disease or condition in a humansubject which benefits from inhibition of p38 MAP kinase activity,comprising administering to a subject in need thereof an effectiveamount of a compound or pharmaceutically acceptable salt as claimed inclaim
 1. 10. A method according to claim 9, wherein said disease orcondition is chronic eosinophilic pneumonia, asthma, COPD, adultrespiratory distress syndrome (ARDS), exacerbation of airwayshyper-reactivity consequent to other drug therapy, or airways diseasethat is associated with pulmonary hypertension.